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EP3184526B1 - Derives de pyrrolo [2,3-d] pyrimidine en tant qu'inhibiteurs de janus kinase - Google Patents

Derives de pyrrolo [2,3-d] pyrimidine en tant qu'inhibiteurs de janus kinase Download PDF

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Publication number
EP3184526B1
EP3184526B1 EP16197502.4A EP16197502A EP3184526B1 EP 3184526 B1 EP3184526 B1 EP 3184526B1 EP 16197502 A EP16197502 A EP 16197502A EP 3184526 B1 EP3184526 B1 EP 3184526B1
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Prior art keywords
pyrrolo
mol
methyl
pyrazol
ethoxy
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EP3184526A1 (fr
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James D. Rodgers
Stacey Shepard
Thomas P. Maduskuie
Haisheng Wang
Nikoo Falahatpisheh
Maria Rafalski
Argyrios G. Arvanitis
Louis Storace
Ravi Kumar Jalluri
Jordan S. Fridman
Krishna Vaddi
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Incyte Holdings Corp
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Incyte Holdings Corp
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Priority to SI200632294T priority Critical patent/SI3184526T1/sl
Priority to PL16197502T priority patent/PL3184526T3/pl
Priority to EP20206996.9A priority patent/EP3838903B1/fr
Priority to RS20181405A priority patent/RS58113B1/sr
Priority to EP18191992.9A priority patent/EP3466953B1/fr
Application filed by Incyte Holdings Corp filed Critical Incyte Holdings Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention provides compounds as defined in the claims that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.
  • Protein kinases are a group of enzymes that regulate diverse, important biological processes including cell growth, survival and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and regeneration, among others. Protein kinases exert their physiological functions through catalyzing the phosphorylation of proteins (or substrates) and thereby modulating the cellular activities of the substrates in various biological contexts. In addition to the functions in normal tissues/organs, many protein kinases also play more specialized roles in a host of human diseases including cancer.
  • oncogenic protein kinases when dysregulated, can cause tumor formation and growth, and further contribute to tumor maintenance and progression ( Blume-Jensen P et al, Nature 2001, 411(6835):355-365 ).
  • oncogenic protein kinases represent one of the largest and most attractive groups of protein targets for cancer intervention and drug development.
  • Protein kinases can be categorized as receptor type and non-receptor type.
  • Receptor tyrosine kinases have an extracellular portion, a transmembrane domain, and an intracellular portion, while non-receptor tyrosine kinases are entirely intracellular.
  • RTK mediated signal transduction is typically initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity, and receptor transphosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response such as cell division, differentiation, metabolic effects, and changes in the extracellular microenvironment
  • RTK subfamilies At present, at least nineteen (19) distinct RTK subfamilies have been identified.
  • One RTK subfamily designated the HER subfamily, includes EGFR, HER2, HER3 and HER4, and bind such ligands as epithelial growth factor (EGF), TGF- ⁇ , amphiregulin, HB-EGF, betacellulin and heregulin.
  • a second family of RTKs designated the insulin subfamily, includes the INS-R, the IGF-1R and the IR-R.
  • a third family, the "PDGF" subfamily includes the PDGF alpha and beta receptors, CSFIR, c-kit and FLK-II.
  • FLK subfamily encompasses the Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (flt-1).
  • FLK-1 Kinase insert Domain-Receptor fetal liver kinase-1
  • FLK-4 fetal liver kinase 4
  • flt-1 fms-like tyrosine kinase 1
  • FGF receptor family FGFR1, FGFR2, FGFR3 and FGFR4
  • Met subfamily c-Met, Ron and Sea
  • the non-receptor type of tyrosine kinases is also composed of numerous subfamilies, including Src, Btk, Abl, Fak, and Jak. Each of these subfamilies can be further subdivided into multiple members that have been frequently linked to oncogenesis.
  • the Src family for example, is the largest and includes Src, Fyn, Lck and Fgr among others.
  • Bolen JB Nonreceptor tyrosine protein kinases. Oncogene. 1993, 8(8):2025-31 .
  • tyrosine kinases both receptor and nonreceptor
  • overexpression or dysregulation of tyrosine kinases may also be of prognostic value.
  • members of the HER family of RTKs have been associated with poor prognosis in breast, colorectal, head and neck and lung cancer.
  • Mutation of c-Kit tyrosine kinase is associated with decreased survival in gastrointestinal stromal tumors. In acute myelogenous leukemia, Flt-3 mutation predicts shorter disease free survival.
  • VEGFR expression which is important for tumor angiogenesis, is associated with a lower survival rate in lung cancer.
  • Tie-1 kinase expression inversely correlates with survival in gastric cancer.
  • BCR-Abl expression is an important predictor of response in chronic myelogenous leukemia and Src tyrosine kinase is an indicator of poor prognosis in all stages of colorectal cancer.
  • Cytokines are low-molecular weight polypeptides or glycoproteins that stimulate biological responses in virtually all cell types. For example, cytokines regulate many of the pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and they can modulate both proinflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens.
  • cytokine binding initiates intracellular signaling cascades that transduce the extracellular signal to the nucleus, ultimately leading to changes in gene expression.
  • the pathway involving the Janus kinase family of protein tyrosine kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs) is engaged in the signaling of a wide range of cytokines.
  • JAKs fulfill this function.
  • Cytokines bind to their receptors, causing receptor dimerization, and this enables JAKs to phosphorylate each other as well as specific tyrosine motifs within the cytokine receptors.
  • STATs that recognize these phosphotyrosine motifs are recruited to the receptor, and are then themselves activated by a JAK-dependent tyrosine phosphorylation event.
  • STATs dissociate from the receptors, dimerize, and translocate to the nucleus to bind to specific DNA sites and alter transcription ( Scott, M. J., C. J. Godshall, et al. (2002). "Jaks, STATs, Cytokines, and Sepsis.” Clin Diagn Lab Immunol 9(6): 1153-9 ).
  • JAK1 also known as Janus kinase-1
  • JAK2 also known as Janus kinase-2
  • JAK3 also known as Janus kinase, leukocyte
  • JAKL also known as Janus kinase-2
  • TYK2 also known as protein-tyrosine kinase 2
  • JAK proteins range in size from 120 to 140 kDa and comprise seven conserved JAK homology (JH) domains; one of these is a functional catalytic kinase domain, and another is a pseudokinase domain potentially serving a regulatory function and/or serving as a docking site for STATs (Scott, Godshall et al. 2002, supra ).
  • JH JAK homology
  • JAK3 is reported to be preferentially expressed in natural killer (NK) cells and not resting T cells, suggesting a role in lymphoid activation ( Kawamura, M., D. W. McVicar, et al. (1994). "Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes.” Proc Natl Acad Sci U S A 91(14): 6374-8 ).
  • cytokine-stimulated immune and inflammatory responses contribute to normal host defense, they also play roles in the pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from hypoactivity and suppression of the immune system, and a hyperactive or inappropriate immune / inflammatory response contributes to the pathology of autoimmune diseases such as rheumatoid and psoriatic arthritis, asthma and systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type I diabetes mellitus, myasthenia gravis, thyroiditis, immunoglobulin nephropathies, myocarditis as well as illnesses such as scleroderma and osteoarthritis ( Ortmann, R.
  • SCID severe combined immunodeficiency
  • Jak1-/-mice are runted at birth, fail to nurse, and die perinatally ( Rodig, S. J., M. A. Meraz, et al. (1998). "Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses.” Cell 93(3): 373-83 ). Jak2-/- mouse embryos are anemic and die around day 12.5 postcoitum due to the absence of definitive erythropoiesis. JAK2-deficient fibroblasts do not respond to IFN gamma, although responses to IFNalpha/beta and IL-6 are unaffected.
  • JAK2 functions in signal transduction of a specific group of cytokine receptors required in definitive erythropoiesis ( Neubauer, H., A. Cumano, et al. (1998). Cell 93(3): 397-409 ; Parganas, E., D. Wang, et al. (1998). Cell 93(3): 385-95 .). JAK3 appears to play a role in normal development and function of B and T lymphocytes. Mutations of JAK3 are reported to be responsible for autosomal recessive severe combined immunodeficiency (SCID) in humans ( Candotti, F., S. A. Oakes, et al. (1997). "Structural and functional basis for JAK3-deficient severe combined immunodeficiency.” Blood 90(10): 3996-4003 ).
  • SCID autosomal recessive severe combined immunodeficiency
  • the JAK/STAT pathway and in particular all four members of the JAK family, are believed to play a role in the pathogenesis of the asthmatic response, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract.
  • T helper 2 T helper 2
  • Signaling through the cytokine receptor IL-4 stimulates JAK1 and JAK3 to activate STAT6, and signaling through IL-12 stimulates activation of JAK2 and TYK2, and subsequent phosphorylation of STAT4.
  • STAT4 and STAT6 control multiple aspects of CD4+ T helper cell differentiation ( Pernis, A. B. and P.
  • JAK/STAT pathway has also been implicated to play a role in inflammatory diseases/conditions of the eye including, but not limited to, ulceris, uveitis, scleritis, conjunctivitis, as well as chronic allergic responses. Therefore, inhibition of JAK kinases may have a beneficial role in the therapeutic treatment of these diseases.
  • JAK/STAT pathway and in particular, JAK3, also plays a role in cancers of the immune system.
  • human CD4+ T cells acquire a transformed phenotype, an event that correlates with acquisition of constitutive phosphorylation of JAKs and STATs.
  • JAK3 and STAT-1, STAT-3, and STAT-5 activation and cell-cycle progression was demonstrated by both propidium iodide staining and bromodeoxyuridine incorporation in cells of four ATLL patients tested.
  • JAK/STAT activation is associated with replication of leukemic cells and that therapeutic approaches aimed at JAK/STAT inhibition may be considered to halt neoplastic growth ( Takemoto, S., J. C. Mulloy, et al. (1997). "Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins.” Proc Natl Acad Sci U S A 94(25): 13897-902 ).
  • Cytokines of the interleukin 6 (IL-6) family which activate the signal transducer gp130, are major survival and growth factors for human multiple myeloma (MM) cells.
  • the signal transduction of gp130 is believed to involve JAK1, JAK2 and Tyk2 and the downstream effectors STAT3 and the mitogen-activated protein kinase (MAPK) pathways.
  • JAK2 inhibitor tyrphostin AG490 JAK2 kinase activity and ERK2 and STAT3 phosphorylation were inhibited.
  • Activation of JAK/STAT in cancers may occur by multiple mechanisms including cytokine stimulation (e.g. IL-6 or GM-CSF) or by a reduction in the endogenous suppressors of JAK signaling such as SOCS (suppressor or cytokine signaling) or PIAS (protein inhibitor of activated STAT) ( Boudny, V., and Kovarik, J., Neoplasm. 49:349-355, 2002 ).
  • cytokine stimulation e.g. IL-6 or GM-CSF
  • SOCS suppressor or cytokine signaling
  • PIAS protein inhibitor of activated STAT
  • JAK inhibition may be therapeutic for the treatment of cancer patients for reasons that extend beyond potential anti-tumor activity.
  • the cachexia indication may gain further mechanistic support with realization that the satiety factor leptin signals through JAKs.
  • JAK3 Janus kinase 3
  • GVHD graft versus host disease
  • JAK3 inhibitor WHI-P-154 prevented these effects arresting the DCs at an immature level, suggesting that immunosuppressive therapies targeting the tyrosine kinase JAK3 may also affect the function of myeloid cells ( Saemann, M. D., C. Diakos, et al. (2003). "Prevention of CD40-triggered dendritic cell maturation and induction of T-cell hyporeactivity by targeting of Janus kinase 3.” Am J Transplant 3(11): 1341-9 ). In the mouse model system, JAK3 was also shown to be an important molecular target for treatment of autoimmune insulin-dependent (type 1) diabetes mellitus.
  • JAK3 inhibitor JANEX-1 exhibited potent immunomodulatory activity and delayed the onset of diabetes in the NOD mouse model of autoimmune type 1 diabetes ( Cetkovic-Cvrlje, M., A. L. Dragt, et al. (2003). "Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice.” Clin Immunol 106(3): 213-25 ).
  • Myeloproliferative disorder includes polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES) and systemic mast cell disease (SMCD).
  • PV polycythemia vera
  • ETD essential thrombocythemia
  • MMM myeloid metaplasia with myelofibrosis
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • HES hypereosinophilic syndrome
  • SMCD systemic mast cell disease
  • the myeloproliferative disorder (such as PV, ET and MMM) are thought to be caused by acquired somatic mutation in hematopoietic progenitors, the genetic basis for these diseases has not been known. However, it has been reported that hematopoietic cells from a majority of patients with PV and a significant number of patients with ET and MMM possess a recurrent somatic activating mutation in the JAK2 tyrosine kinase.
  • JAK2V617F kinase has also been reported that inhibition of the JAK2V617F kinase with a small molecule inhibitor leads to inhibition of proliferation of hematopoietic cells, suggesting that the JAK2 tyrosine kinase is a potential target for pharmacologic inhibition in patients with PV, ET and MMM.
  • Inhibition of the JAK kinases is also envisioned to have therapeutic benefits in patients suffering from skin immune disorders such as psoriasis, and skin sensitization.
  • skin immune disorders such as psoriasis, and skin sensitization.
  • psoriasis vulgaris the most common form of psoriasis, it has been generally accepted that activated T lymphocytes are important for the maintenance of the disease and its associated psoriatic plaques ( Gottling, A.B., et al, Nat Rev Drug Disc., 4:19-34 ).
  • Psoriatic plaques contain a significant immune infiltrate, including leukocytes and monocytes, as well as multiple epidermal layers with increased keratinocyte proliferation.
  • Inhibitors of Janus kinases or related kinases are widely sought and several publications report effective classes of compounds. For example, certain inhibitors are reported in WO 99/65909 , US 2004/0198737 ; WO 2004/099204 ; WO 2004/099205 ; and WO 01/42246 . Heteroaryl substituted pyrroles and other compounds are reported in WO 2004/72063 and WO 99/62908 .
  • autoimmune diseases e.g., multiple sclerosis, rheumatoid arthritis, asthma, type I diabetes, inflammatory bowel disease, Crohn's disease, autoimmune thyroid disorders, Alzheimer's disease
  • diseases involving a hyperactive inflammatory response e.g., eczema
  • allergies e.g., cancer
  • cancer e.g., prostate, leukemia, multiple myeloma
  • immune reactions e.g., skin rash or contact dermatitis or diarrhea caused by other therapeutics, to name a few.
  • the compounds, compositions and methods described herein are directed toward these needs and other ends.
  • the present invention provides a compound which is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, wherein one or more hydrogen atoms are replaced by deuterium; or a pharmaceutically acceptable salt thereof.
  • the present invention further provides compositions comprising a compound which is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, wherein one or more hydrogen atoms are replaced by deuterium, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides, inter alia , compounds as defined in the claims that modulate the activity of one or more JAKs and are useful, for example, in the treatment of diseases associated with JAK expression or activity.
  • the compound of the invention is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, wherein one or more hydrogen atoms are replaced by deuterium, including pharmaceutically acceptable salt forms thereof.
  • substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR'R") n - includes both NR(CR'R") n and -(CR'R") n NR-.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or "aryl” then it is understood that the "alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • alkyl is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl ( e.g ., n-propyl and isopropyl), butyl ( e.g ., n-butyl, isobutyl, t-butyl), pentyl ( e.g ., n-pentyl, isopentyl, neopentyl), and the like.
  • alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • a linking alkyl group is referred to herein as "alkylene.”
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like.
  • a linking alkenyl group is referred to herein as "alkenylene.”
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • a linking alkynyl group is referred to herein as "alkynylene.”
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • halosulfanyl refers to a sulfur group having one or more halogen substituents.
  • Example halosulfanyl groups include pentahalosulfanyl groups such as SF 5 .
  • aryl refers to monocyclic or polycyclic ( e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms.
  • a linking aryl group is referred to herein as "arylene.”
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups.
  • Cycloalkyl groups can include mono- or polycyclic ( e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Cycloalkyl groups also include cycloalkylidenes.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e ., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • a linking cycloalkyl group is referred to herein as "cycloalkylene.”
  • heteroaryl refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic ( e.g., having 2, 3 or 4 fused rings) systems.
  • heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • a linking heteroaryl group is referred to herein as "heteroarylene.”
  • heterocycloalkyl refers to non-aromatic heterocycles including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups include monocyclic and polycyclic ( e.g ., having 2, 3 or 4 fused rings) systems as well as spirocycles.
  • heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like.
  • Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido.
  • Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused ( i.e ., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles.
  • the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom.
  • the heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms.
  • the heterocycloalkyl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms.
  • the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • the heterocycloalkyl group contains 0 to 3 double or triple bonds.
  • the heterocycloalkyl group contains 0 to 2 double or triple bonds.
  • a linking heterocycloalkyl group is referred to herein as "heterocycloalkylene.”
  • halo or halogen includes fluoro, chloro, bromo, and iodo.
  • arylalkyl refers to alkyl substituted by aryl and "cycloalkylalkyl” refers to alkyl substituted by cycloalkyl.
  • An example arylalkyl group is benzyl.
  • heteroarylalkyl refers to alkyl substituted by heteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted by heterocycloalkyl.
  • amino refers to NH 2 .
  • alkylamino refers to an amino group substituted by an alkyl group.
  • dialkylamino refers to an amino group substituted by two alkyl groups.
  • hydroxylalkyl refers to an alkyl group substituted by hydroxyl.
  • cyanoalkyl refers to an alkyl group substituted by cyano.
  • the carbon of the cyano group is typically not counted if a carbon count precedes the term.
  • cyanomethyl is considered herein to be a C 1 cyanoalkyl group.
  • the compounds described herein can be asymmetric ( e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of ⁇ -methyl-benzylamine (e.g ., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1Hand 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention further include hydrates and solvates, as well as anhydrous and non-solvated forms.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds of the invention, and salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which is was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (MeCN) are preferred.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (MeCN) are preferred.
  • MeCN acetonitrile
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999 ).
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • pyrazole-containing cores 1-9 and 1-6 can be synthesized starting with pyrrolo[2,3-b]pyridine or pyrrolo[2,3-b]pyrimidine 1-1.
  • the compound 1-1 can be converted to an active species such as an N-oxide analog ( 1-2 ) by using an oxidant such as m-CPBA.
  • the N-oxide 1-2 can be halogenated with a halogenating agent such as a combination of tetramethylammonium bromide and methanesulfonic anhydride to form a 4-halo compound 1-3 such as a 4-bromo compound while the N-oxide is reduced at the same time.
  • the amine group of the compound 1-3 can be protected by a suitable amine protecting group to afford the protected compound 1-7, which subsequently undergoes a Suzuki coupling with a boric acid 1-8 to afford the pyrazole-containing cores 1-9a which can be further reacted with reagent L-(Y)n-Z (where L is a leaving group) to give compounds 1-9b.
  • the N-oxide 1-2 can be halogenated with a halogenating agent such as MeSO 2 Cl to form a 4-halo compound 1-4 such as a 4-chloro compound while the N-oxide is reduced at the same time.
  • the 4-halo compound 1-4 can be coupled to a bromo-substituted pyrazole compound 1-5 under suitable conditions such as heating to afford the pyrazole-containing core 1-6, which may contain some functional groups such as bromo or cyano suitable for further chemical modification.
  • an imidazole core 1-11 can be synthesized by coupling of the 4-halo compound 1-4 to an imidazole derivative 1-10 under suitable conditions such as heating to afford the imidazole-containing core 1-11, which may contain some functional groups such as bromo or cyano suitable for further chemical modification.
  • pyrazole-containing cores 2-3, 2-5 and 2-6 can be synthesized starting with a bromo-substituted pyrazole derivative 2-1 (a compound 1-6 in Scheme 1 wherein one of R 5 is
  • the bromo-substituted pyrazole derivative 2-1 can be coupled to boron-containing aromatic species such as an aromatic boric acid 2-2 using Suzuki coupling wherein Ar is aryl or heteroaryl, each of which can be optionally substituted by one or more substituents such as alky, aryl, CN, nitro, alkoxy, etc.
  • an alkene- or alkyne-containing compound such as an alkene-containing 2-5 can be obtained by coupling the bromo-substituted pyrazole derivative 2-1 to an unsaturated compound such as an alkene 2-4 in the presence of a metal catalyst such as bis(triphenylphosphine)palladium (II) chloride wherein t can be 0, 1, 2, and the like; and R can be a substituent such as alkyl, aryl, CN, nitro, alkoxy, etc.
  • the alkene group of compound 2-5 can be reduced by hydrogenation to afford the corresponding compound 2-6.
  • imidazole-containing cores 3-7 can be synthesized starting with an N-protected 4-bromo-pyrrolo[2,3-b]pyridine or an N-protected 4-bromo-pyrrolo[2,3-b]pyrimidine 3-1 wherein P is a suitable amine protecting group such as ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ (SEM).
  • P is a suitable amine protecting group such as ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ (SEM).
  • SEM ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇
  • Compound 3-1 can be reacted with a Grignard reagent such as isopropyl magnesium chloride to generate an aromatic anion through ion exchange.
  • chloroacetyl-containing compound such as 2-chloro-N-methoxy-N-methylacetamide 3-2
  • anion will typically afford the chloroacetyl derivative 3-3.
  • the derivative 3-3 can be reacted with an organic acid salt such as a cesium salt R 5 CO 2 Cs to afford a compound 3-4.
  • an organic acid salt such as a cesium salt R 5 CO 2 Cs
  • the compound 3-4 can react with ammonia under suitable conditions such as at a high temperature to form the imidazole ring of the compound 3-5.
  • the free amine nitrogen of the imidazole derivative 3-5 can undergo further modification such as reacting with a compound X-(Y) n -Z where X is a leaving group such as chloro, bromo or iodo so as to afford compound 3-6.
  • the protecting group of compound 3-6 can be removed by an appropriate method according to the nature of the protecting group to yield compound 3-7.
  • further modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to an alcohol, which in turn can be further modified.
  • a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to an alcohol, which in turn can be further modified.
  • thiazole-containing cores 4-3 can be synthesized starting with an N-protected chloroacetyl derivative 4-1 wherein P is a suitable amine protecting group such as SEM.
  • Compound 4-1 can be reacted with a thioamide 4-2 to form the thiazole ring, followed by deprotection of the amine nitrogen of the pyrrole ring by removal of the P group to afford the compound 4-3.
  • thioureas 4-5 (equivalent to compound 4-2 wherein -(Y) n -Z is NR'R"; and R' and R" are H, alkyl, aryl or the like; or R' and R" together with the N atom to which they are attached form a heterocycloalkyl) useful in preparing the thiazole compounds 4-3 can be made from secondary amines 4-4.
  • a secondary amine 4-4 can be reacted with 1,1 '-thiocarbonyldiimidazole; and the resulting intermediate can further be reacted with ammonia to afford a thiourea 4-5.
  • thiazole-containing cores 5-5 can be synthesized starting with a thiazole compound 5-1.
  • the compound 5-1 can be reacted with a metal alkyl such as n-butyl lithium via ion exchange to generate an aromatic anion in situ.
  • the subsequent addition of boric acid trimethyl ester followed by hydrolysis will typically afford the boric acid 5-2.
  • the boric acid 5-2 can undergo Suzuki coupling with an N-protected 4-bromo-pyrrolo[2,3-b]pyridine or an N-protected 4-bromo-pyrrolo[2,3-b]pyrimidine 5-3 wherein P is a suitable amine protecting group such as SEM.
  • the protecting group P of the coupling product 5-4 can be removed by an appropriate method according to the nature of the protecting group to yield the compound 5-5.
  • pyrazole-containing compounds 6-1 can further be modified by substitution on the pyrazole NH group with appropriate reagents.
  • a compound 6-1 wherein P is a suitable amine protecting group such as SEM can be reacted with L-(Y) n -Z where L represents a leaving group such as halo, triflate or the like to afford compound 6-2 under basic condition.
  • L represents a leaving group such as halo, triflate or the like
  • further modification can be made.
  • a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol.
  • compound 6-1 can be reacted with alkene 6-3 (wherein R' and R" can be H, alkyl, cycloalkyl and the like; and Z' can be an electron withdrawing group such as an ester or CN) to afford the compound 6-4. Further, substitution can be made on alkene 6-3 at the alpha position (alpha to Z') to generate a substituted derivatives of product, 6-4 (see, e.g., Example 68).
  • bromo pyrazole containing compounds 7-1 can be further modified by metallation with reagents like butyl lithium and reaction with electrophiles like aldehydes to give the alcohol containing compounds 7-2 which can be deprotected to yield compounds having formula 7-3.
  • metallation with reagents like butyl lithium and reaction with electrophiles like aldehydes to give the alcohol containing compounds 7-2 which can be deprotected to yield compounds having formula 7-3.
  • pyrazole-containing compounds 8-4 and 8-5 can be prepared by reaction of the N-protected bromo compound 8-1 with hydrazine in an appropriate solvent such as N , N -dimethylformamide (DMF) to give the hydrazine intermediate 8-2.
  • the hydrazino intermediate 8-2 is reacted with an appropriately substituted 1,3 bis-aldehyde like 8-3 to give the pyrazole containing compound 8-4.
  • further modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol.
  • a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol.
  • the 1,2,4-oxadiazole compound 9-6 can prepared from the N-protected bromo compound 9-1 by treatment with zinc cyanide in DMF in the presence of a catalyst like bis(tributyl) palladium to give the N-protected cyano compound 9-2.
  • the N-hydroxy carboximidamide compound 9-3 can be prepared by heating the N-protected cyano compound 9-2 with hydroxylamine hydrochloride in an appropriate solvent like ethanol and a base like potassium carbonate at a temperature below the boiling point of the solvent.
  • the N-protected 1,2,4-oxadiazole compound can be prepared by treating the N-hydroxy carboximidamide compound 9-3 with an appropriately substituted acid chloride compound 9-4 in a solvent like pyridine at a sufficient temperature to complete the ring closure. If there are some functional groups present within the Y and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to an ester, which in turn can be further reduced to alcohol.
  • a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to an ester, which in turn can be further reduced to alcohol.
  • the 3- and 4-arylpyrazolo compounds 10-9 can be prepared by reaction of the respective 3-arylpyrazolo compound 10-4 or 4-aryl pyrazolo compound 10-7 with an appropriately substituted bromo compound 10-8 as previously described.
  • the 3-aryl pyrazolo compound 10-4 can be prepared by reacting an appropriately substituted aryl group containing a halogen like bromo or a triflate with the N-protected boronic acid or boronic acid ester pyrazole compound 10-2 under Suzuki-like conditions known in the literature.
  • the N-protecting group of 10-3 can be removed by conditions previously described and known in the literature for removing groups like SEM.
  • the 4-arylpyrazolo compounds 10-7 can be prepared by reacting the appropriately substituted acetophenone compound 10-5 with DMF acetal in DMF at elevated temperatures to give the dimethylamino compound 10-6.
  • the 4-arylpyrazolo compounds 10-7 can be prepared by treating the dimethylamino compound 10-6 with hydrazine in a solvent such as ethanol.
  • the substituted pyrazole compound 11-5 can be prepared by a variety of methods, such as by removing the protecting group e.g ., SEM from compound 11-4 under conditions previously described.
  • the substituted pyrazole N-protected compound 11-4 can be prepared by reaction of the intermediate pyrazole N-protected compound 11-3 with an appropriately substituted alkyl halide, benzyl halide, alkyl sulfonates, e.g., mesylate or tosylate, or other suitable leaving group L, in an appropriate solvent such as MeCN, DMF or tetrahydrofuran (THF), in the presence of a base such a sodium hydride or cesium carbonate.
  • an appropriately substituted alkyl halide, benzyl halide, alkyl sulfonates e.g., mesylate or tosylate, or other suitable leaving group L
  • an appropriate solvent such as MeCN, DMF or tetrahydrofuran (
  • the N-aryl pyrazole 11-4 (wherein Y is aromatic) may be prepared by reacting the intermediate pyrazole 11-3 with an appropriately substituted aryl boronic acid in a solvent such as dichloromethane (DCM) with copper acetate and pyridine.
  • DCM dichloromethane
  • the N-aryl pyrazole 11-4 (wherein Y is aromatic) can be prepared by reacting the intermediate pyrazole 11-3 with an appropriately substituted aryl-fluoride in a solvent such as DMF at elevated temperature.
  • the substituted pyrazole compounds 11-4 (wherein Z is a group such as nitrile or ester and Y is at least two carbons) can be prepared by the reaction of intermediate pyrazole 11-3 with an appropriately substituted acrylate, acrylonitrile or other Michael-like acceptors in a solvent such as DMF in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or triethylamine (TEA) and at a temperature below the boiling point of the solvent.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • TAA triethylamine
  • pyrazole 12-1 wherein P is a suitable amine protecting group such as SEM can be reacted with an alkyne-containing conjugate acceptor such as 12-2, wherein Z is an electron-withdrawing group (for example, -CN) optionally in the presence of a base (DBU or K 2 CO 3 and the like) in a solvent such as DMF or MeCN for variable lengths of time to provide olefin-containing adducts 12-3.
  • a base DBU or K 2 CO 3 and the like
  • Compounds represented by the formula 12-3 can be deprotected by appropriate methods according to the nature of the protecting group used to afford compounds 12-4.
  • oxazole- or thiazole-containing compounds 13-6 can be prepared starting with N-protected 4-chloro-pyrrolo[2,3-b]pyrimidine 13-1 wherein P is a suitable amine protecting group such as SEM.
  • Oxazole- or thiazole-containing products of formula 13-2 can be prepared by palladium-catalyzed coupling of 13-1 with oxazole or thiazole.
  • a metal alkyl such as n-butyllithium
  • Ketones 13-4 can be caused to react with a variety of reagents such as diethyl (cyanomethyl)phosphonate or triethylphosphonoacetate in the presence of a base like potassium tert-butoxide followed by reduction (including hydrogenation or a copper-hydride catalyzed conjugate reduction), or with reagents such as tosylmethyl isocyanide to provide products of formula 13-5 wherein Z is an electron-withdrawing group such as ester or -CN. If there are functional groups present within the R group or encompassed by the Z group, further modification can be made, and such appropriate further modifications will be recognized by one skilled in the art. Compounds 13-5 can be deprotected by appropriate methods according to the nature of the protecting group used to afford their corresponding deprotected counterparts 13-6.
  • reagents such as diethyl (cyanomethyl)phosphonate or triethylphosphonoacetate
  • a base like potassium tert-butoxide followed by reduction (including
  • aminothiazole-containing cores 14-5 can be synthesized starting with thiazole-containing core 14-1 wherein P is a suitable amine protecting group such as SEM.
  • the compound 14-1 can be treated with a metal alkyl such as n-butyllithium to generate the aromatic anion in situ to which can be added a suitable source of electrophilic halogen such as carbon tetrabromide to afford the halogenated derivative 14-2.
  • the protecting group P of 14-2 can be removed by an appropriate method according to the nature of the protecting group to yield product 14-3.
  • the compound 14-3 can be reacted with amines 14-4 at elevated temperatures in a suitable solvent such as DMF to afford the compound 14-5.
  • pyrrole-containing cores 15-4 can be synthesized starting with N-protected 4-chloro-pyrrolo[2,3-b]pyrimidine 15-1 wherein P is a suitable amine protecting group such as DEM (diethoxymethyl).
  • P is a suitable amine protecting group such as DEM (diethoxymethyl).
  • the compound 15-1 can be reacted with 1-(triisopropylsilyl)pyrrole-3-boronic acid under Suzuki coupling conditions to afford the simultaneously pyrrole-deprotected core 15-2.
  • Pyrrole-containing compounds 15-2 can be reacted with alkenes 15-3 containing an electron-withdrawing group Z (such as -CN) in the presence of an appropriate base (such as DBU) at various temperatures (e.g., between room temperature and 40° C) followed by an in situ or separate deprotection step that is suitable for the selected protecting group to afford compounds 15-4.
  • an appropriate base such as DBU
  • a substituted pyrazole compound containing a sulfone or sulfoxide functionality as in 16-6 can be prepared by a variety of methods, such as starting with an appropriately substituted bromo thiophenyl ether 16-2.
  • Thioether 16-2 may be readily prepared by alkylation of the thiophenol 16-1 with an alkyl halide, mesylate or the like using a base like DBU, potassium carbonate or sodium hydride.
  • the cinnamyl nitrile 16-3 may be prepared by Heck chemistry and the like, using palladium acetate and triphenylphosphine in DMF at an appropriate temperature with acrylonitrile.
  • the SEM protected intermediate 16-4 may be prepared by methods previously described for performing the Michael like addition of the pyrazole core to an appropriately substituted ⁇ - ⁇ unsaturated nitrile like 16-3.
  • MCPBA m-chloroperbenzoic acid
  • the sulfur oxidation may be performed on compounds 16-2 or 16-3 depending on the compatibility of the substitution in the synthetic scheme.
  • substituted pyrazole compounds containing a sulfonamide functionality can be prepared by a variety of methods. For example, one may start with an appropriately substituted bromo phenyl sulfonamide 17-2, where R c and R d are suitable substituents.
  • a compound 17-2 may be readily prepared by reaction of the bromo phenyl sulfonyl chloride 17-1 and an appropriately substituted amine such as an aniline, or a primary or secondary amine in a suitable solvent such as DCM, THF or pyridine.
  • the cinnamyl nitrile 17-3 may be prepared by Heck chemistry or the like, using palladium acetate and triphenylphosphine in DMF at an appropriate temperature with acrylonitrile.
  • the final compounds 17-6 where R c and R d are part of the sulfonamide functional group may be prepared by methods analogous to those described in Scheme 16 starting with the cinnamyl nitrile 17-3.
  • substituted pyrazole compounds containing an alpha-allyl cyclopentylmethylene functionality can be prepared by, for example, reacting a pyrazole 18-3, wherein P is a suitable amine protecting group such as SEM and X is N or C, with a cyclopentylacrylate ester 18-4 to form the ester 18-5.
  • the ester 18-5 may then be reduced to the corresponding aldehyde, 18-6, for example, by the two-step procedure of reducing to the alcohol and selectively oxidizing the intermediate alcohol to the aldehyde, e.g ., via a Swern oxidation..
  • the aldehyde, 18-6 may then be converted to the corresponding olefin, 18-7, for example by reaction with a Wittig reagent.
  • the olefin 18-7 may then be deprotected, as described earlier, to produce the formula 18-7 compound.
  • the intermediate, 18-4 may be prepared, for example as shown in Scheme 18, stearting with cyclopentylaldehyde.
  • the cyanoguanidine derivative 19-6 can be prepared starting from substituted pyrazole compounds such as pyrazole 18-3, wherein P is a suitable protecting group such as SEM and X is N or C.
  • a compound 18-3 may, for example, be reacted with olefin 19-1, prepared by Horner-Wadsworth Emmons reaction of the corresponding Boc-protected piperidone, in the presence of a suitable basic catalyst, in a suitable solvent, to form 19-2.
  • the intermediate 19-2 is deprotected using a suitable deprotection reaction, to provide the amine compound 19-3, which then reacts selectively with a cyanoimidocarbonate reagent such as 19-4, in a polar solvent at a suitable temperature, for example, about 20 °C to give a cyanoimidocarbamate such as 19-5, which can then be reacted with any of a variety of amines at elevated temperature to give product 19-6.
  • a suitable deprotection reaction to provide the amine compound 19-3, which then reacts selectively with a cyanoimidocarbonate reagent such as 19-4, in a polar solvent at a suitable temperature, for example, about 20 °C to give a cyanoimidocarbamate such as 19-5, which can then be reacted with any of a variety of amines at elevated temperature to give product 19-6.
  • the intermediate compounds 20-5 and 20-6 may be prepared by a variety of methods in the literature, for example, methods such as are outlined in Scheme 20.
  • the intermediate compound 20-3 may be prepared by reaction of the aldehyde compound 20-1 with an appropriately substituted Wittig reagent or Horner Emmons reagents to give the ⁇ - ⁇ unsubstituted ester 20-3.
  • 20-3 may be prepared by a Heck-like reaction with an appropriately substituted aryl bromide 20-2 and an acrylic ester in the presence of a palladium reagent at elevated temperatures.
  • the compound 20-4 may be prepared by methods previously described for the Michael-like addition of an appropriately substituted pyrrole 18-3 on the ⁇ - ⁇ unsaturated ester compound 20-3.
  • the aldehyde compound 20-5 may be prepared by reduction of the ester compound 20-4 with reagents such as diisobutyl aluminium hydride at low temperatures such as about -78 °C in an appropriate solvent.
  • the aldehyde compound 20-5 can be further reduced to the corresponding alcohol compound 20-6 with reagents such as sodium borohydride in methanol.
  • the alcohol compound 20-6 may be prepared directly by reduction of the ester 20-4 with reagents such as lithium aluminium hydride in appropriate solvent and at appropriate temperatures.
  • the compounds 21-2 and 21-3 may be prepared by using a variety of methods in the literature, such as, for example, methods outlined in Scheme 21.
  • the olefin compound 21-1 may be prepared by the reaction of aldehyde compound 20-5 with an appropriately substituted Wittig reagent or Horner Emmons reagents using a base such as sodium hydride or potassium t-butoxide in an appropriate solvent and conducted at temperature.
  • the olefin compound compound 21-1 may be reduced to the saturated compound 21-2, for example, using hydrogenation conditions well known in the literature, e.g., hydrogen in the presence of palladium on carbon in a solvent such as methanol.
  • the acetylenic compound 21-3 may be prepared by methods previously described, or by reaction of the aldehyde 20-5 with Bestmann-Ohira reagent ( E. Quesada et al, Tetrahedron, 62 (2006) 6673-6680 ) as described in the literature.
  • the alcohol compound 20-6 in Scheme 20 may be oxidized to the aldehyde 20-5 with methods well known in the literature, e.g., Swern oxidation conditions, followed by reaction with the Bestmann-Ohira reagent, wherein this reaction sequence may be carried out either as a one pot two-step reaction sequence, or in two separate reaction steps.
  • the compounds 22-1 and 22-3 may be prepared by using a variety of methods in the literature, for example, via methods outlined in Scheme 22.
  • the oxygen-substituted compound 22-1 may be prepared, for example, by reaction of an appropriately substituted alcohol 20-6 (in Scheme 20), wherein X is N or C, and P is a protecting group, with a base such as sodium hydride and an appropriate agent such as an alkyl iodide, carbonate, or isocyanate, carried out in a suitable solvent and at a suitable temperature.
  • the alcohol group on the compound 20-6 may be converted to a leaving group LG, as in compound 22-2, where the leaving group can be, for example, bromide or mesylate.
  • a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be reduced to an alcohol, which in turn can be further modified.
  • an OH group can be converted into a better leaving group such as mesylate, which in turn is suitable for nucleophilic substitution, such as by CN.
  • Compounds of the invention can modulate activity of one or more Janus kinases (JAKs).
  • the term "modulate” is meant to refer to an ability to increase or decrease the activity of one or more members of the JAK family of kinases.
  • compounds of the invention can be used in methods of modulating a JAK by contacting the JAK with any one or more of the compounds or compositions described herein.
  • compounds of the present invention can act as inhibitors of one or more JAKs.
  • compounds of the present invention can act to stimulate the activity of one or more JAKs.
  • the compounds of the invention can be used to modulate activity of a JAK in an individual in need of modulation of the receptor by administering a modulating amount of a compound of Formula Ia, Ib, or Ic.
  • JAKs to which the present compounds bind and/or modulate include any member of the JAK family.
  • the JAK is JAK1, JAK2, JAK3 or TYK2.
  • the JAK is JAK1 or JAK2.
  • the JAK is JAK2.
  • the JAK is JAK3.
  • the compounds of the invention can be selective.
  • selective is meant that the compound binds to or inhibits a JAK with greater affinity or potency, respectively, compared to at least one other JAK.
  • the compounds of the invention are selective inhibitors of JAK1 or JAK2 over JAK3 and/or TYK2.
  • the compounds of the invention are selective inhibitors of JAK2 (e.g., over JAK1, JAK3 and TYK2).
  • a compound which is selective for JAK2 over JAK3 and which is useful in the treatment of cancer can offer the additional advantage of having fewer immunosuppressive side effects.
  • Selectivity can be at least about 5-fold, 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold. Selectivity can be measured by methods routine in the art. In some embodiments, selectivity can be tested at the Km of each enzyme. In some embodiments, selectivity of compounds of the invention for JAK2 over JAK3 can be determined by the cellular ATP concentration.
  • the compound of the present invention may be used in methods of treating a JAK-associated disease or disorder in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof.
  • a JAK-associated disease can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the JAK, including over-expression and/or abnormal activity levels.
  • a JAK-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating JAK activity.
  • JAK-associated diseases include diseases involving the immune system including, for example, organ transplant rejection (e.g., allograft rejection and graft versus host disease).
  • organ transplant rejection e.g., allograft rejection and graft versus host disease.
  • JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, autoimmune thyroid disorders, and the like.
  • the autoimmune disease is an autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP).
  • JAK-associated diseases include allergic conditions such as asthma, food allergies, atopic dermatitis and rhinitis.
  • Further examples of JAK-associated diseases include viral diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV).
  • EBV Epstein Barr Virus
  • HBV Human Papilloma Virus
  • HPV Human Papilloma Virus
  • JAK-associated diseases or conditions include skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis).
  • skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis).
  • certain substances including some pharmaceuticals when topically applied can cause skin sensitization.
  • co-administration or sequential administration of at least one JAK inhibitor of the invention together with the agent causing unwanted sensitization can be helpful in treating such unwanted sensitization or dermatitis.
  • the skin disorder is treated by topical administration of at least one JAK inhibitor of the invention.
  • the JAK-associated disease is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, melanoma etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia, or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma.
  • CTCL cutaneous T-cell lymphoma
  • Example cutaneous T-cell lymphomas include Sezary syndrome and mycosis fungoides.
  • JAK-associated diseases can further include those characterized by expression of a mutant JAK2 such as those having at least one mutation in the pseudo-kinase domain (e.g., JAK2V617F).
  • a mutant JAK2 such as those having at least one mutation in the pseudo-kinase domain (e.g., JAK2V617F).
  • JAK-associated diseases can further include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like.
  • MPDs myeloproliferative disorders
  • PV polycythemia vera
  • ET essential thrombocythemia
  • MMM myeloid metaplasia with myelofibrosis
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • HES hypereosinophilic syndrome
  • SMCD systemic mast cell disease
  • JAK-associated diseases include inflammation and inflammatory diseases.
  • Example inflammatory diseases include inflammatory diseases of the eye (e.g., ulceris, uveitis, scleritis, conjunctivitis, or related disease), inflammatory diseases of the respiratory tract (e.g., the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the lower respiratory tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myopathy such as myocarditis, and other inflammatory diseases.
  • the JAK inhibitors described herein can further be used to treat ischemia reperfusion injuries or a disease or condition related to an inflammatory ischemic event such as stroke or cardiac arrest.
  • the JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue such as that resulting from or associated with cancer.
  • the JAK inhibitors described herein can further be used to treat restenosis, sclerodermitis, or fibrosis.
  • the JAK inhibitors described herein can further be used to treat conditions associated with hypoxia or astrogliosis such as, for example, diabetic retinopathy, cancer, or neurodegeneration. See, e.g., Dudley, A.C. et al. Biochem. J. 2005, 390(Pt 2):427-36 and Sriram, K. et al. J. Biol. Chem. 2004, 279(19):19936-47 . Epub 2004 Mar 2.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a JAK with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a JAK, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the JAK.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:
  • One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well as Bcr-Ab1, Flt-3, RAF and FAK kinase inhibitors such as, for example, those described in WO 2006/056399 , or other agents can be used in combination with the compounds of the present invention for treatment of JAK-associated diseases, disorders or conditions.
  • the one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
  • Example chemotherapeutic include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.
  • proteosome inhibitors e.g., bortezomib
  • thalidomide thalidomide
  • revlimid thalidomide
  • DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.
  • Example steroids include coriticosteroids such as dexamethasone or prednisone.
  • Example Bcr-Ab1 inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184 , WO 04/005281 , EP2005/009967 , EP2005/010408 , and U.S. Ser. No. 60/578,491 .
  • Example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347 , WO 03/099771 , and WO 04/046120 .
  • Example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444 .
  • Example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980 , WO 04/056786 , WO 03/024967 , WO 01/064655 , WO 00/053595 , and WO 01/014402 .
  • one or more JAK inhibitors of the invention can be used in combination with a chemotherapeutic in the treatment of cancer, such as multiple myeloma, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects.
  • additional pharmaceutical agents used in the treatment of multiple myeloma can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).
  • Further additional agents used in the treatment of multiple myeloma include Bcr-Ab1, Flt-3, RAF and FAK kinase inhibitors.
  • Additive or synergistic effects are desirable outcomes of combining a JAK inhibitor of the present invention with an additional agent.
  • resistance of multiple myeloma cells to agents such as dexamethasone may be reversible upon treatment with a JAK inhibitor of the present invention.
  • the agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • a corticosteroid such as dexamethasone is administered to a patient in combination with at least one JAK inhibitor where the dexamethasone is administered intermittently as opposed to continuously.
  • combinations of one or more JAK inhibitors of the invention with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplant or stem cell transplant.
  • the compounds of the invention can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary ( e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • topical including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal
  • oral or parenteral e.g., by in
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g ., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful.
  • compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers (excipients).
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
  • additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
  • Another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating JAK in tissue samples, including human, and for identifying JAK ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes JAK assays that contain such labeled compounds.
  • the present invention further includes isotopically-labeled compounds of the invention.
  • An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature ( i.e ., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound.
  • a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I , 35 S and 82 Br.
  • the present invention can further include synthetic methods for incorporating radio-isotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of invention.
  • a labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e ., test compound
  • a test compound which is labeled can be evaluated for its ability to bind a JAK by monitoring its concentration variation when contacting with the JAK, through tracking of the labeling.
  • a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a JAK (i.e ., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the JAK directly correlates to its binding affinity.
  • the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
  • kits useful for example, in the treatment or prevention of JAK-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • Example 67 is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile.
  • Other examples are described for reference. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results.
  • the compounds of the Examples have been found to be JAK inhibitors according to at least one assay described herein.
  • the reaction mixture was allowed to warm to room temperature (rt) and stirred overnight, then was cooled at 0 °C, filtered and washed with ethyl acetate three times to give 10.94 g wet solid.
  • the wet solid (8.45 g) was then suspended in water (35 mL), and to the suspension was added 13 mL of sat. Na 2 CO 3 dropwise, and the resulting mixture was stirred at room temperature overnight.
  • the mixture was then cooled at 0° C, filtered and washed with water (x4) to give 3.55 g of pale purple solid which was dried at 40° C overnight to give the desired product (2.47 g, 44.4% yield).
  • Step 1 3-Methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole-4-carboxylic acid .
  • the reaction mixture was then partitioned between ethyl acetate and water, and washed sequentially with sat. NaHCO 3 and brine.
  • the organic phase was dried and evaporated to give 49 mg of the crude product as an orange oil/glass.
  • the crude product was chromatographed with 75-100% ethyl acetate/hexanes, sample in DCM. Collected 25 mg of the purified product as a colorless glass/oil (50% yield).
  • Step 1 4-[1-(3-Methoxy-1-methylpropyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine
  • Step 1 4-1-[1-Methyl-3-(1H-pyrazol-1-yl)propyl]-1H-pyrazol-4-yl-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine
  • N-Methyl-N-propylamine (0.501 mL, 0.00488 mol) was added to a solution of 1,1'-thiocarbonyldiimidazole (0.957 g, 0.00537 mol) in THF (9 mL, 0.1 mol), and the resulting solution was stirred for 16 hours.
  • the intermediate from the reaction mixture was isolated by silica gel chromatography (5% MeOH in DCM) and this intermediate was stirred with ammonia (7M solution in MeOH) (6 mL) for 48 hours. The solvent was removed in vacuo. N-methyl-N-propylthiourea was obtained after flash column chromatography (4% MeOH in DCM).
  • Tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.000018 mol) was added and the resulting mixture was heated to 125 °C for 30 minutes.
  • the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H 2 O containing 0.1% TFA) to afford 12 mg of a yellow solid containing the desired product as the major component.
  • the mixture was stirred in TFA (1 mL) for 1 hour. Then excess TFA was removed in vacuo and the resulting residue was stirred with 2 mL MeOH, 0.5 mL NH 4 OH and 100 ⁇ L ethylenediamine for 16 hours.
  • Example 55 Ethyl 2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoate trifluoroacetate salt (55a) AND 2-Methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoic acid (55b)
  • chiral separation was performed by one of the following methods: A) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with 15% ethanol in hexanes); B) The separation was performed on the deprotected free base by preparative chiral HPLC (OD-H column, eluting with 15% ethanol in hexanes); C) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H column, eluting with 10% ethanol in hexanes); D) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H column, eluting with 10% ethanol in hexanes);
  • Example 65 (3R)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]hexanenitrile trifluoroacetate salt and (3S)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]hexanenitrile trifluoroacetate salt
  • Tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.00036 mol) was added and the reaction was heated to 125 °C for 30 min. The mixture was allowed to cool then diluted with ethyl acetate. The diluted reaction mixture was washed with water, brine, dried over Na 2 SO 4 and concentrated to give a solution in a small volume of DMF (about 2-3 mL). Water was added, causing the material to form a gum on the walls of the flask. Then water was decanted, and the solids were dissolved in ethyl acetate. The solution was dried over Na 2 SO 4 , and concentrated in vacuo to afford a yellow solid.
  • Example 69 4- ⁇ 1-[(1S)-1-Methylbutyl]-1H-pyrazol-4-yl ⁇ -7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt and 4- ⁇ 1-[(1R)-1-Methylbutyl]-1H-pyrazol-4-yl ⁇ -7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt
  • Example 69a The analogs in Table 5a were prepared according to the above method described for Example 69a.
  • Example 69b a conjugate acceptor was used and prepared as described in Perkin Trans. 1, 2000, (17), 2968-2976 , and Steps 4&5 were performed before Step 3.
  • Table 5a Ex. No.
  • Examples 69e and 69f in Table 5b were prepared by a method analogous to that described above for Example 69d, with unsaturated nitriles prepared either according to published literature procedures, or by the method in Step 1.
  • Table 5b Ex. No. Structure Name MS (ES) (M+1) 69e 3-ethyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile 295 69f 1-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclopropylacetonitrile 265
  • the crude reaction mixture was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H 2 O containing 0.15% NH 4 OH) and again by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H 2 O containing 0.1% TFA) to yield the desired product as the trifluoroacetate salt (30 mg, 68%).
  • Example 87 (3R)-3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-oxazol-2-yl]-propanenitrile, and (3S)-3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-oxazol-2-yl]propanenitrile
  • n-Butyllithium in hexane (1.6 M, 0.30 mL) was added slowly dropwise to a -78 °C solution of 4-(1,3-oxazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (140.0 mg, 0.44 mmol) in THF (10.0 mL). After 20 minutes, 1.0 M zinc dichloride in ether (0.53 mL) was added. The reaction mixture was then stirred for 60 min at 0 °C. Following this, copper(I) iodide (84 mg, 0.44 mmol) was added, and this mixture was allowed to stir for 10 minutes.
  • the reaction was concentrated and purified by prep LCMS (C18 column eluting with a gradient of ACN/H 2 O containing 0.15% NH 4 OH) to give 125 mg of a white foam.
  • the white foam was triturated with MTBE ( ⁇ 1.5 mL). The resulting solid was filtered, washed and dried to give 80 mg of the product (32% yield).
  • Step 1 3-(Dimethoxymethyl)cyclopentanecarbaldehyde.
  • Step 3 3-[3-(Dimethoxymethyl)cyc / opentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile.
  • Step 4 3-(3-Formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile.
  • the combined organic phase was washed with water, then sat'd NaHCO 3 , then sat'd NaCl, and then was dried over MgSO 4 and filtered and stripped to dryness to leave the crude product as a mixture of diastereomers.
  • Step 5 3-3-[(E,Z)-(Hydroxyimino)methyl]cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile.
  • Step 7 3-(2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)-cyclopentane-carbonitrile trifluoroacetate.
  • Step 1 3-[3-(Hydroxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile
  • the reaction was quenched by cautious addition of IN HCl (3 drops) and methanol (1 mL), followed by addition of aqueous NaHCO 3 and CHCl 3 .
  • the phases were separated and the aqueous phase was washed with additional CHCl 3 .
  • the combined organic phase was washed with sat'd NaCl, dried over MgSO 4 and reduced to dryness.
  • the residue was purified by column chromatography to obtain the product as a mixture of diastereomers (37.4 mg, 74%).
  • Example 100 1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole (100a) and 2-(1H-pyrrolo[2,3-b]-pyridin-4-yl)-2H-indazole (100b)
  • the reaction was allowed to cool to rt, taken up in ethyl acetate and washed with water saturated sodium carbonate, brine, dried over magnesium sulfate and concentrated to give an oil.
  • the crude product was purified by flash column chromatography (FCC) on silica gel, eluting with a hexane: ethyl acetate gradient to give the product (0.25 gm) as a colorless oil.
  • Tetrakis(triphenylphosphine)palladium(0) 53 mg, 0.000046 mol was added and nitrogen was bubbled for 3 min.
  • the reaction was heated in a microwave at 80 °C for 30 min, then allowed to cool to rt and taken up in water and ethyl acetate.
  • the organic layer was dried over MgSO 4 , filtered and concentrated to give a crude product, which was purified by FCC on silica gel, eluting with EtOAc/Hexanes (1:5) to give 3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazol4-yl)benzonitrile, as an oil, LC /MS (M+H) + : 300.
  • Example 170 2-[1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole
  • Step 1 4-[4-(1-Phenylviny / )-1H-pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine
  • Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled for 3 min. The reaction was heated in a sealed tube in the microwave at 100 °C for 30 min. The reaction was allowed to cool to rt and partitioned between ethyl acetate and water.
  • Tetrakis(triphenylphosphine)palladium(0) (0.080 g, 0.000069 mol) was added, and again the mixture was degassed with nitrogen for 5 min. The reaction was heated in sealed tube to 100 °C in a microwave for 30 minutes. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a crude residue.
  • the reaction was degassed with nitrogen, then tetrakis(triphenylphosphine)-palladium(0) (0.08 g, 0.00007 mol) was added and in a sealed tube the reaction was heated to 120 °C oil bath. The reaction was heated for 30 minutes, allowed to cool and then taken up in ethyl acetate. The reaction mixture was washed with brine, dried over magnesium sulfate and concentrated to give an oil.
  • Example 250 4- ⁇ 1-[(1 R )-1-Methylbutyl]-1H-pyrazol-4-yl ⁇ -1H-pyrrolo[2,3-b]pyridine (250a) and 4- ⁇ 1-[(1 S )-1-Methylbutyl]-1H-pyrazol-4-yl ⁇ -1H-pyrrolo[2,3-b]pyridine (250b)
  • Step 1 Dimethyl 3-[4-(7- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate
  • Step 2 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanedioic acid
  • the reaction was then concentrated to remove the DCM and the resulting DMF solution was diluted with water to precipitate the product.
  • the solid precipitate was collected and washed with water to give a dark solid.
  • the solid was then dissolved in DCM and washed with brine, dried over magnesium sulfate and concentrated to give a very dark oily residue. The residue was taken up in DCM, and hexane was added until the solution became slightly cloudy.
  • Step 1 3-(6-Chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propane-nitrile
  • Step 2 5-2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylpyridine-2-carbo-nitrile trifluoroacetate
  • the reaction mixture was heated in a sealed tube at 170 °C for 15 minutes in a microwave (Personal Chemistry). After cooling to room temperature, the solids were filtered, rinsed with DMF and the combined solvent was concentrated in vacuo. The residue was triturated with hexanes (3x), and hexanes washes were discarded.
  • Step 1 3-[4-(7-[2-(Trirnethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol
  • Step 2 3-[4-(7-[2-(Trimethylsilyl)ethoxy]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diyl dimethanesulfonate
  • Step 3 4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanedinitrile
  • Step 4 4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanedinitrile
  • the reaction was sealed and heated at 170 °C for 15 minutes in a microwave (Personal Chemistry). The reaction was allowed to cool and the solids were filtered off. The combined DMF fractions were concentrated in vacuo. The residue was triturated with ethyl acetate-hexanes 2:8, then with ethyl ether to removed by-products. The crude product was purified by preparative HPLC eluting with a water : acetontrile gradient containing 0.2% TFA to give the racemic title compound (43 mg, 59.65%).
  • Step 1 3-(3-Nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile
  • Step 1 (3-2-Cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylphenyl)acetamide
  • Step 6 5-[(E)-(Hydroxyimino)methyl]-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile
  • Step 7 4-(2-Cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)thiophene-2-carbonitrile
  • Step 8 4-(2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)thiophene-2-carbonitrile trifluoroacetate
  • Example 472 3-[3-(Morpholin-4-ylcarbonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate
  • Step 1 3-(2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)benzoic acid
  • Step 2 3-[3-(Morpholine-1-ylcarbonyl)phenyl]-3-[4-(7- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]propanenitrile
  • Step 3 3-[3-(Morpholin-4-ylcarhonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate
  • Step 1 3-(5-Phenylpyridin-3-yl)-3-[4-(7-12-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile
  • Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled through the reaction again. The reaction was heated at 80 °C in oil bath for 1hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (50 mg, 80%) as a crude product. MS (ES): 522 (M+1).
  • Step 2 3-(5-Pherylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate
  • Step 1 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl-3-5-[(trimethylsilyl)ethynyl]pyridin-3-ylpropanenitrile
  • Step 2 3-(5-Ethynylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate
  • Step 1 3-[5-(Phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile
  • Step 2 3-[5-(Phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile trifluoroacetate
  • Step 4 3-(5-Morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile
  • Step 5 3-(5-Morpholin-4-ylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile
  • Example 496 3-[5-(Phenylsulfinyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, and Example 497: 3-[5-(Phenylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile
  • Step 1 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal
  • Step 1 Methyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentyl carbonate
  • Step 1 (1E)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-7-yl]pentanal oxime
  • Step 1 (1E)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal O-methyloxime and (1Z)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal O-methyloxime
  • Step 1 4-[1-(4,4-Dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine
  • Example 506 4-[1-(1-Ethylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate
  • Step 1 4-[1-(1-Ethylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

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Claims (6)

  1. Composé, qui est le 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, dans lequel un ou plusieurs atomes d'hydrogène sont remplacés par le deutérium ; ou sel pharmaceutiquement acceptable de celui-ci.
  2. Composition pharmaceutique comprenant un composé selon la revendication 1, ou un sel pharmaceutiquement acceptable de celui-ci et un véhicule pharmaceutiquement acceptable.
  3. Composé selon la revendication 1, qui est le (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, dans lequel un ou plusieurs atomes d'hydrogène sont remplacés par le deutérium ; ou sel pharmaceutiquement acceptable de celui-ci.
  4. Composition pharmaceutique comprenant un composé selon la revendication 3, ou sel pharmaceutiquement acceptable de celui-ci et véhicule pharmaceutiquement acceptable.
  5. Composé selon la revendication 1, qui est le (3S)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, dans lequel un ou plusieurs atomes d'hydrogène sont remplacés par le deutérium ; ou sel pharmaceutiquement acceptable de celui-ci.
  6. Composition pharmaceutique comprenant un composé selon la revendication 5, ou sel pharmaceutiquement acceptable de celui-ci et véhicule pharmaceutiquement acceptable.
EP16197502.4A 2005-12-13 2006-12-12 Derives de pyrrolo [2,3-d] pyrimidine en tant qu'inhibiteurs de janus kinase Active EP3184526B1 (fr)

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RS20181405A RS58113B1 (sr) 2005-12-13 2006-12-12 Derivati pirolo[2,3-d]pirimidina kao inhibitori janus kinaze
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EP18191992.9A Active EP3466953B1 (fr) 2005-12-13 2006-12-12 Dérivé de pyrrolo[2,3-b]pyrimidine en tant qu'inhibiteur de janus kinase
EP20206996.9A Active EP3838903B1 (fr) 2005-12-13 2006-12-12 Dérivé du pyrrolo[2,3-b]pyrimidine en tant qu'inhibiteur de la janus kinase
EP11152714.9A Active EP2474545B1 (fr) 2005-12-13 2006-12-12 Pyrrolo[2,3-b]pyridines et pyrrolo[2,3-b]pyrimidines à substitution hétéroaryle en tant qu'inhibiteurs de la janus kinase
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Families Citing this family (432)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005105814A1 (fr) * 2004-04-28 2005-11-10 Incyte Corporation Inhibiteurs tetracycliques de janus kinases
AR054416A1 (es) 2004-12-22 2007-06-27 Incyte Corp Pirrolo [2,3-b]piridin-4-il-aminas y pirrolo [2,3-b]pirimidin-4-il-aminas como inhibidores de las quinasas janus. composiciones farmaceuticas.
JP2009508832A (ja) * 2005-09-16 2009-03-05 アストラゼネカ アクチボラグ グルコキナーゼ活性化剤としてのヘテロ二環式化合物
CA2621261C (fr) * 2005-09-22 2014-05-20 Incyte Corporation Inhibiteurs tetracycliques de janus kinases
US8133900B2 (en) * 2005-11-01 2012-03-13 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
US8604042B2 (en) * 2005-11-01 2013-12-10 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
NZ592990A (en) * 2005-11-01 2013-01-25 Targegen Inc Bi-aryl meta-pyrimidine inhibitors of kinases
DK3184526T3 (en) * 2005-12-13 2019-01-14 Incyte Holdings Corp PYRROLO [2,3-D] PYRIMIDINE DERIVATIVES AS A JANUS-KINASE INHIBITOR
MX2008008320A (es) * 2005-12-23 2008-09-03 Smithkline Beecham Corp Inhibidores de azaindol de aurora cinasas.
EP2003132B1 (fr) * 2006-04-03 2014-03-05 Astellas Pharma Inc. Dérivés d'oxadiazole en tant qu'agonistes du S1P1
KR20090018895A (ko) * 2006-04-05 2009-02-24 버텍스 파마슈티칼스 인코포레이티드 야누스 키나제의 억제제로서 유용한 데아자푸린
CA2668652C (fr) 2006-11-20 2018-06-12 President And Fellows Of Harvard College Inhibiteurs de canaux ioniques potentiel-dependants a utiliser dans le traitement de la douleur et du prurit
EP2121692B1 (fr) 2006-12-22 2013-04-10 Incyte Corporation Hétérocycles substitués servant d'inhibiteurs de janus kinases
CL2008001709A1 (es) * 2007-06-13 2008-11-03 Incyte Corp Compuestos derivados de pirrolo [2,3-b]pirimidina, moduladores de quinasas jak; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como cancer, psoriasis, artritis reumatoide, entre otras.
DK2740731T3 (en) 2007-06-13 2016-04-11 Incyte Holdings Corp CRYSTALLINE SALTS OF JANUSKINASEINHIBITOREN (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-CYCLOPENTYLPROPANNITRIL
EP2176249A2 (fr) * 2007-07-02 2010-04-21 Boehringer Ingelheim International GmbH Nouveaux composés chimiques
WO2009032338A1 (fr) * 2007-09-09 2009-03-12 University Of Florida Research Foundation Agents thérapeutiques à base d'apratoxine : mécanisme et procédés de traitement
WO2009049028A1 (fr) * 2007-10-09 2009-04-16 Targegen Inc. Composés de pyrrolopyrimidine et leur utilisation en tant qu'inhibiteurs des janus kinases
US8183245B2 (en) * 2007-10-25 2012-05-22 Merck Sharp & Dohme Corp. Pyrazine substituted pyrrolopyridines as inhibitors of JAK and PDK1
WO2009064835A1 (fr) * 2007-11-16 2009-05-22 Incyte Corporation 4-pyrazolyl-n-arylpyrimidin-2-amines et 4-pyrazolyl-n-hétéroarylpyrimidin-2-amines en tant qu'inhibiteurs de janus kinase
CA2714177A1 (fr) * 2008-02-06 2009-08-13 Novartis Ag Composes heterocycliques
WO2009114552A1 (fr) * 2008-03-10 2009-09-17 The Board Of Trustees Of The Leland Stanford Junior University Composés hétéroaryle, compositions et procédés d’utilisation dans le traitement du cancer
BRPI0909040B8 (pt) 2008-03-11 2021-05-25 Incyte Holdings Corp derivados de azetidina e ciclobutano, seus usos, e composição
JP2011518221A (ja) * 2008-04-21 2011-06-23 メルク・シャープ・エンド・ドーム・コーポレイション Ｊａｎｕｓキナーゼの阻害剤
JP2011518836A (ja) * 2008-04-24 2011-06-30 インサイト・コーポレイション 大環状化合物およびそれらのキナーゼ阻害剤としての使用
AR071717A1 (es) 2008-05-13 2010-07-07 Array Biopharma Inc Pirrolo[2,3-b]piridinas inhibidoras de quinasas chk1 y chk2,composiciones farmaceuticas que las contienen,proceso para prepararlas y uso de las mismas en el tratamiento y prevencion del cancer.
WO2009155156A1 (fr) * 2008-06-18 2009-12-23 Merck & Co., Inc. Inhibiteurs de janus kinases
EP2296475A4 (fr) * 2008-06-20 2014-03-05 Genentech Inc Composés triazolopyridine inhibiteurs de jak kinase et procédés
CA2727036C (fr) * 2008-06-20 2017-03-21 Genentech, Inc. Composes triazolopyridine inhibiteurs de jak kinase et procedes
CL2009001884A1 (es) * 2008-10-02 2010-05-14 Incyte Holdings Corp Uso de 3-ciclopentil-3-[4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)propanonitrilo, inhibidor de janus quinasa, y uso de una composición que lo comprende para el tratamiento del ojo seco.
AT507187B1 (de) 2008-10-23 2010-03-15 Helmut Dr Buchberger Inhalator
JOP20190230A1 (ar) * 2009-01-15 2017-06-16 Incyte Corp طرق لاصلاح مثبطات انزيم jak و المركبات الوسيطة المتعلقة به
WO2010085597A1 (fr) * 2009-01-23 2010-07-29 Incyte Corporation Composés macrocycliques et leur utilisation en tant qu'inhibiteurs des kinases
AU2010249443B2 (en) 2009-05-22 2015-08-13 Incyte Holdings Corporation 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octane- or heptane-nitrile as JAK inhibitors
MY156727A (en) * 2009-05-22 2016-03-15 Incyte Corp N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
CA2764885C (fr) 2009-06-08 2018-05-15 Takeda Pharmaceutical Company Limited Composes de dihydropyrrolonaphtyridinone comme inhibiteurs de jak
EP2448938B9 (fr) 2009-06-29 2015-06-10 Incyte Corporation Pyrimidinones comme inhibiteurs de pi3k
JP6205133B2 (ja) 2009-07-10 2017-09-27 プレジデント アンド フェローズ オブ ハーバード カレッジ 抗炎症剤としての恒久的に荷電したナトリウムおよびカルシウムチャンネルブロッカー
TWI466885B (zh) 2009-07-31 2015-01-01 Japan Tobacco Inc 含氮螺環化合物及其醫藥用途
TW201113285A (en) 2009-09-01 2011-04-16 Incyte Corp Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
US9029359B2 (en) 2009-09-04 2015-05-12 Biogen Idec Ma, Inc. Heteroaryl Btk inhibitors
BR112012005382A2 (pt) * 2009-09-10 2016-03-29 Hoffmann La Roche inibidores de jak
JP6012468B2 (ja) 2009-10-02 2016-10-25 アヴェクシン エーエス 抗炎症性２−オキソチアゾールおよび２−オキソオキサゾール
KR101921850B1 (ko) * 2009-10-09 2018-11-23 인사이트 홀딩스 코포레이션 3-（4-（7Ｈ-피롤로〔2,3-ｄ〕피리미딘-4-일）-1Ｈ-피라졸-1-일）-3-사이클로펜틸프로판니트릴의 하이드록실, 케토 및 글루쿠로나이드 유도체
US8389728B2 (en) * 2009-11-06 2013-03-05 The Arizona Board Of Regents Pollen tube stimulants from Arabidopsis pistils
CA2790070C (fr) * 2010-02-18 2018-03-06 Incyte Corporation Derives de cyclobutane et de methylcyclobutane comme inhibiteurs de janus kinases
WO2011109217A2 (fr) * 2010-03-02 2011-09-09 Immunodiagnostics, Inc. Méthodes de traitement prophylactique ou thérapeutique de troubles viraux dépendants de l'arn polymérase par administration d'inhibiteurs de la jak2 kinase
AU2011224484A1 (en) 2010-03-10 2012-09-27 Incyte Holdings Corporation Piperidin-4-yl azetidine derivatives as JAK1 inhibitors
AU2015205858B2 (en) * 2010-03-10 2017-04-13 Incyte Holdings Corporation Piperidin-4-yl azetidine derivatives as jak1 inhibitors
US8962596B2 (en) * 2010-04-14 2015-02-24 Array Biopharma Inc. 5,7-substituted-imidazo[1,2-C]pyrimidines as inhibitors of JAK kinases
US9133123B2 (en) 2010-04-23 2015-09-15 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
AR081626A1 (es) 2010-04-23 2012-10-10 Cytokinetics Inc Compuestos amino-piridazinicos, composiciones farmaceuticas que los contienen y uso de los mismos para tratar trastornos musculares cardiacos y esqueleticos
AR081331A1 (es) 2010-04-23 2012-08-08 Cytokinetics Inc Amino- pirimidinas composiciones de las mismas y metodos para el uso de los mismos
MY161078A (en) 2010-05-21 2017-04-14 Incyte Holdings Corp Topical formulation for a jak inhibitor
KR101541086B1 (ko) * 2010-08-20 2015-08-03 허치슨 메디파르마 리미티드 피롤로피리미딘 화합물 및 그 용도
JP5852658B2 (ja) * 2010-09-24 2016-02-03 ザ リージェンツ オブ ザ ユニバーシティー オブ ミシガン デユビキチナーゼ阻害剤およびその使用方法
AU2011320565A1 (en) * 2010-10-28 2013-05-23 Innocrin Pharmaceuticals, Inc. Metalloenzyme inhibitor compounds
WO2012060847A1 (fr) 2010-11-07 2012-05-10 Targegen, Inc. Compositions et procédés de traitement de la myélofibrose
WO2012068440A1 (fr) * 2010-11-19 2012-05-24 Incyte Corporation Pyrrolopyridines et pyrrolopyrimidines à substitution hétérocyclique utilisées en tant qu'inhibiteurs des jak
EA036970B1 (ru) * 2010-11-19 2021-01-21 Инсайт Холдингс Корпорейшн Применение {1-{1-[3-фтор-2-(трифтометил)изоникотиноил] пиперидин-4-ил}-3-[4-(7h-пирроло[2,3-d]пиримидин-4-ил)-1н-пиразол-1-ил]азетидин-3-ил}ацетонитрила для лечения заболеваний, связанных с активностью jak1
EP2640723A1 (fr) 2010-11-19 2013-09-25 Incyte Corporation Dérivés pyrrolopyridine et pyrrolopyrimidine à substitution cyclobutyle utilisés comme inhibiteurs des jak
EP2651930B1 (fr) * 2010-12-16 2015-10-28 Boehringer Ingelheim International GmbH Inhibiteurs biarylamide de production de leukotriènes
EP2655374B1 (fr) 2010-12-20 2019-10-23 Incyte Holdings Corporation N-(1-(phényl substitué)éthyl)-9h-purin-6-amines en tant qu'inhibiteurs de pi3k
HUE026804T2 (en) 2011-02-11 2016-07-28 Batmark Ltd Inhaler component
ES2547916T3 (es) 2011-02-18 2015-10-09 Novartis Pharma Ag Terapia de combinación de inhibidores de mTOR/JAK
WO2012116151A2 (fr) 2011-02-24 2012-08-30 Cephalon, Inc. Composés soufrés aromatiques substitués et procédés de leur utilisation
CA2830882C (fr) 2011-03-22 2021-03-16 Dinesh Barawkar Composes tricycliques substitues; compositions et applications medicinales correspondantes
US8759380B2 (en) 2011-04-22 2014-06-24 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
MX2013013331A (es) * 2011-05-17 2014-10-17 Principia Biopharma Inc Derivados de azaindol como inhibidores de tirosina-cinasas.
EP2720696B1 (fr) 2011-06-14 2016-05-25 Novartis AG Combinaison de panobinostat et de ruxolitinib dans le traitement du cancer tel qu'un néoplasme myéloprolifératif
KR20140040819A (ko) 2011-06-20 2014-04-03 인사이트 코포레이션 Ｊａｋ 저해제로서의 아제티디닐 페닐, 피리딜 또는 피라지닐 카르복스아미드 유도체
ES2548414T3 (es) 2011-07-08 2015-10-16 Novartis Ag Novedosos derivados de pirrolo pirimidina
HK1198579A1 (en) 2011-08-10 2015-04-30 Novartis Pharma Ag Jak p13k/mtor combination therapy
TW201313721A (zh) 2011-08-18 2013-04-01 Incyte Corp 作為ｊａｋ抑制劑之環己基氮雜環丁烷衍生物
PL3513793T3 (pl) 2011-09-02 2021-09-20 Incyte Holdings Corporation Heterocykloaminy jako inhibitory pi3k
UA111854C2 (uk) 2011-09-07 2016-06-24 Інсайт Холдінгс Корпорейшн Способи і проміжні сполуки для отримання інгібіторів jak
ES2640911T3 (es) * 2011-09-22 2017-11-07 Merck Sharp & Dohme Corp. Cicloalquilnitrilpirazolcarboxamidas como inhibidores de la quinasa Janus
AU2012323399A1 (en) * 2011-10-12 2014-05-29 Array Biopharma Inc. 5,7-substituted-imidazo[1,2-c]pyrimidines
US9089574B2 (en) 2011-11-30 2015-07-28 Emory University Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections
US10821111B2 (en) 2011-11-30 2020-11-03 Emory University Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections
US8993756B2 (en) * 2011-12-06 2015-03-31 Merck Sharp & Dohme Corp. Pyrrolopyrimidines as janus kinase inhibitors
AR090548A1 (es) 2012-04-02 2014-11-19 Incyte Corp Azaheterociclobencilaminas biciclicas como inhibidores de pi3k
US20130310340A1 (en) 2012-05-16 2013-11-21 Rigel Pharmaceuticals, Inc. Method of treating muscular degradation
WO2013173720A1 (fr) 2012-05-18 2013-11-21 Incyte Corporation Dérivés de pyrrolopyridine et de pyrrolopyrimidine substitués par un pipéridinylcyclobutyle à titre d'inhibiteurs jak
EA201492287A1 (ru) 2012-06-15 2015-07-30 Консерт Фармасьютикалс, Инк. Дейтерированные производные руксолитиниба
JP6280546B2 (ja) 2012-06-26 2018-02-14 デル マー ファーマシューティカルズ ジアンヒドロガラクチトール、ジアセチルジアンヒドロガラクチトール、ジブロモズルシトール、又はこれらの類似体若しくは誘導体を用いた、遺伝子多型又はａｈｉ１の調節不全若しくは変異を有する患者におけるチロシンキナーゼインヒビター抵抗性悪性腫瘍を処置するための方法
WO2014016396A1 (fr) 2012-07-27 2014-01-30 Ratiopharm Gmbh Formes galéniques orales destinées à une libération modifiée comprenant du ruxolitinib
RU2666538C2 (ru) * 2012-08-02 2018-09-11 НЕРВИАНО МЕДИКАЛ САЙЕНСИЗ С.р.л. Замещенные пирролы, активные в качестве ингибиторов киназ
WO2014045305A1 (fr) 2012-09-21 2014-03-27 Advinus Therapeutics Limited Composés tricycliques condensés substitués, compositions et applications médicales correspondantes
JP6139690B2 (ja) * 2012-10-26 2017-05-31 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ブルートンチロシンキナーゼの阻害剤
UA117572C2 (uk) 2012-11-01 2018-08-27 Інсайт Холдинґс Корпорейшн Трициклічні конденсовані похідні тіофену як інгібітори jak
PH12020551186B1 (en) 2012-11-15 2024-03-20 Incyte Holdings Corp Sustained-release dosage forms of ruxolitinib
US9310374B2 (en) 2012-11-16 2016-04-12 Redwood Bioscience, Inc. Hydrazinyl-indole compounds and methods for producing a conjugate
US10130632B2 (en) 2012-11-27 2018-11-20 Beth Israel Deaconess Medical Center, Inc. Methods for treating renal disease
JP6353460B2 (ja) * 2012-12-06 2018-07-04 バルーク エス．ブランバーグ インスティチュート Ｈｂｖ感染に対する抗ウイルス剤としての官能化ベンズアミド誘導体
US9260426B2 (en) * 2012-12-14 2016-02-16 Arrien Pharmaceuticals Llc Substituted 1H-pyrrolo [2, 3-b] pyridine and 1H-pyrazolo [3, 4-b] pyridine derivatives as salt inducible kinase 2 (SIK2) inhibitors
JP6371312B2 (ja) 2013-01-29 2018-08-08 アヴェクシン エーエス 坑炎症および抗腫瘍２−オキソチアゾール化合物ならびに２−オキソチオフェン化合物
JP2016507066A (ja) 2013-02-08 2016-03-07 インスティテュート フォー ミエローマ アンド ボーン キャンサー リサーチ 多発性骨髄腫、慢性リンパ球性白血病、およびｂ細胞非ホジキンリンパ腫の改善された診断方法、予後予測方法、およびモニタリング方法
CN104982091B (zh) * 2013-02-12 2018-03-13 柯尼卡美能达株式会社 有机电致发光元件及照明装置
JP6397831B2 (ja) 2013-03-06 2018-09-26 インサイト・ホールディングス・コーポレイションＩｎｃｙｔｅ Ｈｏｌｄｉｎｇｓ Ｃｏｒｐｏｒａｔｉｏｎ Ｊａｋ阻害剤の製造方法及びその中間体
US20140343034A1 (en) 2013-04-25 2014-11-20 Japan Tobacco Inc. Skin barrier function improving agent
TWI719401B (zh) 2013-05-17 2021-02-21 美商英塞特公司 作為jak抑制劑之聯吡唑衍生物
KR20160045081A (ko) 2013-08-07 2016-04-26 인사이트 코포레이션 Jak1 억제제용 지속 방출 복용 형태
TW201529074A (zh) * 2013-08-20 2015-08-01 Incyte Corp 在ｃ-反應蛋白含量較高之實體腫瘤患者中的存活益處
US10570204B2 (en) 2013-09-26 2020-02-25 The Medical College Of Wisconsin, Inc. Methods for treating hematologic cancers
US9611263B2 (en) 2013-10-08 2017-04-04 Calcimedica, Inc. Compounds that modulate intracellular calcium
EP3057972A4 (fr) * 2013-10-15 2017-03-22 V Jin Nouvelles compositions, leurs utilisations et procédés de préparation
RU2016125133A (ru) 2013-11-27 2018-01-09 Новартис Аг Комбинированная терапия, включающая применение ингибиторов jak, cdk и pim
MD4649C1 (ro) 2013-12-05 2020-04-30 Pfizer Inc. Pirol[2,3-d]pirimidinil, pirol[2,3-b]pirazinil şi pirol[2,3-d]piridinil acrilamide
JP6367545B2 (ja) * 2013-12-17 2018-08-01 コンサート ファーマシューティカルズ インコーポレイテッド ルキソリチニブの重水素化誘導体
KR102261733B1 (ko) * 2013-12-18 2021-06-04 콘서트 파마슈티컬즈, 인크. 룩소리티닙의 중수소화된 유도체
CN104725380B (zh) * 2013-12-18 2019-06-28 康塞特医药品有限公司 卢索替尼的氘代衍生物
JOP20200094A1 (ar) 2014-01-24 2017-06-16 Dana Farber Cancer Inst Inc جزيئات جسم مضاد لـ pd-1 واستخداماتها
JOP20200096A1 (ar) 2014-01-31 2017-06-16 Children’S Medical Center Corp جزيئات جسم مضاد لـ tim-3 واستخداماتها
US9340540B2 (en) 2014-02-28 2016-05-17 Nimbus Lakshmi, Inc. TYK2 inhibitors and uses thereof
CN106456773A (zh) * 2014-02-28 2017-02-22 因赛特公司 用于治疗骨髓增生异常综合征的jak1抑制剂
EP3660050A1 (fr) 2014-03-14 2020-06-03 Novartis AG Molécules d'anticorps anti-lag-3 et leurs utilisations
LT3129021T (lt) 2014-04-08 2020-12-10 Incyte Corporation B ląstelių piktybiškumo gydymas jak ir pi3k inhibitorių deriniu
MX2016014192A (es) 2014-04-30 2017-05-01 Incyte Corp Procesos para preparar un inhibidor de cinasas de janus 1 (jak1) y nuevas formas de este.
RU2564891C1 (ru) * 2014-05-27 2015-10-10 Александр Александрович Кролевец Способ получения нанокапсул цитокининов
WO2015184087A2 (fr) * 2014-05-28 2015-12-03 Institute For Myeloma & Bone Cancer Research Effets anti-cancéreux d'inhibiteurs de jak2 en combinaison avec des dérivés de thalidomide et des glucocorticoïdes
WO2015184305A1 (fr) 2014-05-30 2015-12-03 Incyte Corporation Traitement de la leucémie neutrophile chronique (cnl) et de la leucémie myéloïde chronique atypique (acml) par des inhibiteurs de jak1
CN105218548A (zh) * 2014-06-09 2016-01-06 上海海和药物研究开发有限公司 一种新型杂环化合物及其制备方法和作为激酶抑制剂的用途
WO2015191677A1 (fr) 2014-06-11 2015-12-17 Incyte Corporation Dérivés d'hétéroarylaminoalkylphényle bicycliques à titre d'inhibiteurs de pi3k
WO2016010886A1 (fr) * 2014-07-14 2016-01-21 Signal Pharmaceuticals, Llc Méthodes de traitement d'un cancer à l'aide de composés de pyrrolopyrimidine substitués, compositions de ceux-ci
NZ629796A (en) * 2014-07-14 2015-12-24 Signal Pharm Llc Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use
GB201413695D0 (en) 2014-08-01 2014-09-17 Avexxin As Compound
LT3179991T (lt) 2014-08-11 2021-11-10 Acerta Pharma B.V. Terapiniai btk inhibitoriaus ir bcl-2 inhibitoriaus deriniai
US20170239351A1 (en) 2014-08-11 2017-08-24 Acerta Pharma B.V. Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, a PD-1 Inhibitor, and/or a PD-L1 Inhibitor
WO2016024232A1 (fr) 2014-08-11 2016-02-18 Acerta Pharma B.V. Combinaisons thérapeutiques d'un inhibiteur de la btk, d'un inhibiteur de la pi3k, d'un inhibiteur de la jak-2 et/ou d'un inhibiteur de la cdk 4/6
CN117164657A (zh) 2014-08-12 2023-12-05 莫纳什大学 定向淋巴的前药
WO2016026974A1 (fr) * 2014-08-21 2016-02-25 Ratiopharm Gmbh Sel d'oxalate de ruxolitinib
KR20170060042A (ko) 2014-09-13 2017-05-31 노파르티스 아게 Alk 억제제의 조합 요법
CN105524067A (zh) * 2014-09-28 2016-04-27 江苏柯菲平医药股份有限公司 4-取代吡咯并[2,3-d]嘧啶化合物及其用途
US20170209574A1 (en) 2014-10-03 2017-07-27 Novartis Ag Combination therapies
MA41044A (fr) 2014-10-08 2017-08-15 Novartis Ag Compositions et procédés d'utilisation pour une réponse immunitaire accrue et traitement contre le cancer
CN114920840A (zh) 2014-10-14 2022-08-19 诺华股份有限公司 针对pd-l1的抗体分子及其用途
WO2016063294A2 (fr) * 2014-10-20 2016-04-28 Msn Laboratories Private Limited Procédé de préparation de phosphate de (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile et de ses polymorphes
RU2708459C2 (ru) 2014-10-29 2019-12-09 БайсиклРД Лимитед Бициклические пептидные лиганды, специфичные для мт1-ммр
GB2535427A (en) 2014-11-07 2016-08-24 Nicoventures Holdings Ltd Solution
CZ2014773A3 (cs) 2014-11-10 2016-05-18 Zentiva, K.S. Soli (3R)-3-cyklopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propannitrilu
CN105777754B (zh) * 2014-12-16 2019-07-26 北京赛林泰医药技术有限公司 吡咯并嘧啶化合物
RS63963B1 (sr) 2015-02-27 2023-03-31 Incyte Holdings Corp Postupak pripreme pi3k inhibitora
EP3262049B1 (fr) 2015-02-27 2022-07-20 Nimbus Lakshmi, Inc. Inhibiteurs de tyk2 et leurs utilisations
JO3746B1 (ar) 2015-03-10 2021-01-31 Aduro Biotech Inc تركيبات وطرق لتنشيط الإشارات المعتمدة على "منبه أو تحفيز جين انترفيرون"
KR101859170B1 (ko) * 2015-04-17 2018-05-17 광주과학기술원 트리아졸 화합물 및 이의 용도
ES2734048T3 (es) * 2015-04-29 2019-12-04 Wuxi Fortune Pharmaceutical Co Ltd Inhibidores de Janus cinasas (JAK)
US9732097B2 (en) 2015-05-11 2017-08-15 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
US9840503B2 (en) 2015-05-11 2017-12-12 Incyte Corporation Heterocyclic compounds and uses thereof
WO2016183063A1 (fr) 2015-05-11 2016-11-17 Incyte Corporation Formes cristallines d'un inhibiteur de pi3k
WO2017004134A1 (fr) 2015-06-29 2017-01-05 Nimbus Iris, Inc. Inhibiteurs d'irak et leurs utilisations
CZ2015496A3 (cs) 2015-07-14 2017-01-25 Zentiva, K.S. Krystalické formy solí (3R)-3-cyklopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propannitrilu a jejich příprava
WO2017011720A1 (fr) * 2015-07-16 2017-01-19 Signal Pharmaceuticals, Llc 4-((4(cyclopentyloxy)-5-méthylbenzo[d]oxazol-6-yl)-17h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-méthoxy-n-méthylbenzamide sous forme solide, compositions correspondantes et procédés d'utilisation correspondants
PL3317301T3 (pl) 2015-07-29 2021-11-15 Novartis Ag Terapie skojarzone zawierające cząsteczki przeciwciał przeciw lag-3
EP3316902A1 (fr) 2015-07-29 2018-05-09 Novartis AG Polythérapies comprenant des molécules d'anticorps contre tim -3
US20180222982A1 (en) 2015-07-29 2018-08-09 Novartis Ag Combination therapies comprising antibody molecules to pd-1
JP6833811B2 (ja) 2015-08-03 2021-02-24 プレジデント アンド フェローズ オブ ハーバード カレッジ 荷電イオンチャネル遮断薬及び使用方法
WO2017027717A1 (fr) 2015-08-12 2017-02-16 Incyte Corporation Composés de pyrimidine fusionnés bicycliques utilisés en tant qu'inhibiteurs de tam
WO2017035366A1 (fr) * 2015-08-26 2017-03-02 Incyte Corporation Dérivés de type pyrrolo-pyrimidine utilisés comme inhibiteurs des tam
WO2017040757A1 (fr) 2015-09-02 2017-03-09 Nimbus Lakshmi, Inc. Inhibiteurs de tyk2 et leurs utilisations
JP7118888B2 (ja) 2015-09-08 2022-08-16 モナッシュ ユニバーシティ リンパ指向性プロドラッグ
WO2017044720A1 (fr) 2015-09-11 2017-03-16 Navitor Pharmaceuticals, Inc. Analogues de la rapamycine et leurs utilisations
GB2542838B (en) 2015-10-01 2022-01-12 Nicoventures Trading Ltd Aerosol provision system
AU2016342027B2 (en) 2015-10-23 2021-05-13 Navitor Pharmaceuticals, Inc. Modulators of Sestrin-GATOR2 interaction and uses thereof
MY198562A (en) 2015-11-03 2023-09-05 Janssen Biotech Inc Antibodies specifically binding pd-1 and their uses
US10065963B2 (en) 2015-11-06 2018-09-04 Incyte Corporation Heterocyclic compounds as PI3K-γ inhibitors
AU2016354009B2 (en) 2015-11-09 2021-05-20 R.P. Scherer Technologies, Llc Anti-CD22 antibody-maytansine conjugates and methods of use thereof
RU2601410C1 (ru) * 2015-11-13 2016-11-10 ЗАО "Р-Фарм" {3-[(7H-ПИРРОЛО[2,3-d]ПИРИМИДИН-4-ИЛ)АЗОЛИЛ]АЗЕТИДИН-3-ИЛ}АЦЕТОНИТРИЛЫ В КАЧЕСТВЕ ИНГИБИТОРОВ ЯНУС КИНАЗ
EP3389664A4 (fr) 2015-12-14 2020-01-08 Raze Therapeutics Inc. Inhibiteurs de caféine de mthfd2 et leurs utilisations
CN108368115B (zh) * 2015-12-15 2020-01-03 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物的盐
JP2019503349A (ja) 2015-12-17 2019-02-07 ノバルティス アーゲー Ｐｄ−１に対する抗体分子およびその使用
CA3007421A1 (fr) 2015-12-17 2017-06-22 Novartis Ag Combinaison d'un inhibiteur de c-met avec une molecule d'anticorps dirigee contre pd-1 et ses utilisations
US9630968B1 (en) 2015-12-23 2017-04-25 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
ES2882118T3 (es) * 2015-12-31 2021-12-01 Chia Tai Tianqing Pharmaceutical Group Co Ltd Procedimiento de síntesis de ruxolitinib
JP7011600B2 (ja) 2016-01-12 2022-01-26 ジェイムズ リチャード ベレンソン， 被験体の免疫状態をモニタリングするための改善された方法
CZ201629A3 (cs) 2016-01-22 2017-08-02 Zentiva, K.S. Krystalické modifikace solí (3R)-3-cyklopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propannitrilu a způsoby jejich přípravy
JP6770580B2 (ja) * 2016-01-26 2020-10-14 杭州華東医薬集団生物医薬有限公司Ｈａｎｇｚｈｏｕ Ｈｕａｄｏｎｇ Ｍｅｄｉｃｉｎｅ Ｇｒｏｕｐ Ｂｉｏｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． ピロロピリミジン５員環アザ環状誘導体およびその利用
CN105541891B (zh) * 2016-02-04 2017-11-28 东南大学 巴瑞替尼的中间体及其制备方法及由该中间体制备巴瑞替尼的方法
HUE055197T2 (hu) 2016-03-09 2021-11-29 Raze Therapeutics Inc 3-Foszfoglicerát-dehidrogenáz inhibitorok és alkalmazásuk
EP4234552A3 (fr) 2016-03-09 2023-10-18 Raze Therapeutics, Inc. Inhibiteurs de la 3-phosphoglycérate déshydrogénase et leurs utilisations
GB201604318D0 (en) 2016-03-14 2016-04-27 Avexxin As Combination therapy
EP3436461B1 (fr) 2016-03-28 2023-11-01 Incyte Corporation Composés de pyrrolotriazine en tant qu'inhibiteurs de tam
JP2019510785A (ja) 2016-04-08 2019-04-18 エックス４ ファーマシューティカルズ， インコーポレイテッド 癌を処置する方法
US10561659B2 (en) 2016-05-04 2020-02-18 Concert Pharmaceuticals, Inc. Treatment of hair loss disorders with deuterated JAK inhibitors
EP3464266B1 (fr) 2016-06-01 2021-10-20 Bayer Animal Health GmbH Indazole substitutes utiles dans le traitement ou la prevention de maladies allergiques et/ou inflammatoires chez l'animal
CN107759600A (zh) * 2016-06-16 2018-03-06 正大天晴药业集团股份有限公司 作为jak抑制剂的吡咯并嘧啶化合物的结晶
CN107513069A (zh) * 2016-06-16 2017-12-26 正大天晴药业集团股份有限公司 手性吡咯并嘧啶化合物的制备方法
CN107513067A (zh) 2016-06-16 2017-12-26 北京赛林泰医药技术有限公司 含有取代环戊基的吡咯并嘧啶化合物
US10988465B2 (en) 2016-06-21 2021-04-27 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
WO2017223243A1 (fr) 2016-06-21 2017-12-28 X4 Pharmaceuticals, Inc. Inhibiteurs de cxcr4 et leurs utilisations
CA3027498A1 (fr) 2016-06-21 2017-12-28 X4 Pharmaceuticals, Inc. Inhibiteurs de cxcr4 et leurs utilisations
EP3478687B1 (fr) 2016-06-30 2024-03-20 Daewoong Pharmaceutical Co., Ltd. Dérivés de pyrazolopyrimidine comme inhibiteurs de kinase
EP3507367A4 (fr) 2016-07-05 2020-03-25 Aduro BioTech, Inc. Composés dinucléotidiques cycliques d'acide nucléique bloqué et leurs utilisations
CN109790158B (zh) * 2016-07-26 2022-06-24 苏州隆博泰药业有限公司 作为jak抑制剂杂环化合物，该化合物的盐类及其治疗用途
RU2019108280A (ru) 2016-08-24 2020-09-25 Аркьюл, Инк. Аминопирролопиримидиноновые соединения и способы их применения
JOP20190024A1 (ar) 2016-08-26 2019-02-19 Gilead Sciences Inc مركبات بيروليزين بها استبدال واستخداماتها
IT201600092051A1 (it) * 2016-09-13 2018-03-13 Alessandro Antonelli Composto medicale per il trattamento di tumori della tiroide
CN109952303B (zh) 2016-10-14 2022-10-21 林伯士拉克许米公司 Tyk2抑制剂及其用途
WO2018075937A1 (fr) 2016-10-21 2018-04-26 Nimbus Lakshmi, Inc. Inhibiteurs de tyk2 et leurs utilisations
EP3538091A4 (fr) 2016-11-08 2020-06-10 Navitor Pharmaceuticals, Inc. Inhibiteurs de la phényl amino pipéridine mtorc et leurs utilisations
AU2017368050A1 (en) 2016-11-29 2019-06-20 Puretech Lyt, Inc. Exosomes for delivery of therapeutic agents
US11091451B2 (en) 2016-12-05 2021-08-17 Raze Therapeutics, Inc. SHMT inhibitors and uses thereof
RU2644155C1 (ru) * 2016-12-12 2018-02-08 Закрытое акционерное общество "Р-Фарм" (ЗАО "Р-Фарм") 2-(3-(4-(7H-пирроло[2,3-d]пиримидин-4-ил)-1H-пиразол-1-ил)-1-(этилсульфонил)азетидин-3-ил)ацетонитрила геминафтилдисульфонат в качестве ингибитора Янус киназ
CN110603261A (zh) 2016-12-23 2019-12-20 拜斯科阿迪有限公司 具有新型键结构的肽衍生物
US10624968B2 (en) 2017-01-06 2020-04-21 Bicyclerd Limited Compounds for treating cancer
EA039352B1 (ru) * 2017-01-19 2022-01-17 Сучжоу Лонгбайотек Фармасьютикалз Ко., Лтд. Соединение в качестве селективного ингибитора jak и его соли и терапевтическое применение
IL269036B2 (en) 2017-03-08 2023-03-01 Nimbus Lakshmi Inc tyk2 inhibitors, uses and methods for their production
EP3375778A1 (fr) 2017-03-14 2018-09-19 Artax Biopharma Inc. Dérivés d'aryl-pipéridine
EP3375784A1 (fr) 2017-03-14 2018-09-19 Artax Biopharma Inc. Dérivés d'aza-dihydro-acridone
WO2018191146A1 (fr) 2017-04-10 2018-10-18 Navitor Pharmaceuticals, Inc. Inhibiteurs de rheb à base d'hétéroaryle et leurs utilisations
JOP20180036A1 (ar) 2017-04-18 2019-01-30 Vifor Int Ag أملاح لمثبطات فروبورتين جديدة
CN116370448A (zh) 2017-04-26 2023-07-04 纳维托制药有限公司 Sestrin-gator2相互作用的调节剂及其用途
US10857196B2 (en) 2017-04-27 2020-12-08 Bicycletx Limited Bicyclic peptide ligands and uses thereof
UY37695A (es) 2017-04-28 2018-11-30 Novartis Ag Compuesto dinucleótido cíclico bis 2’-5’-rr-(3’f-a)(3’f-a) y usos del mismo
MX2019014054A (es) 2017-05-23 2020-02-05 Theravance Biopharma R&D Ip Llc Profarmacos de glucuronida de inhibidores de la cinasa janus.
WO2018231944A1 (fr) 2017-06-13 2018-12-20 Berenson James R Méthodes de diagnostic, de pronostic et de surveillance de cancers à tumeur solide
KR20200021087A (ko) 2017-06-22 2020-02-27 노파르티스 아게 Cd73에 대한 항체 분자 및 이의 용도
EP3642240A1 (fr) 2017-06-22 2020-04-29 Novartis AG Molécules d'anticorps dirigées contre cd73 et utilisations correspondantes
US10899798B2 (en) 2017-06-26 2021-01-26 Bicyclerd Limited Bicyclic peptide ligands with detectable moieties and uses thereof
CN107298680A (zh) * 2017-07-12 2017-10-27 海门华祥医药科技有限公司 一种4‑氯‑7‑氮杂吲哚的生产工艺
US11046698B2 (en) 2017-07-28 2021-06-29 Nimbus Lakshmi, Inc. TYK2 inhibitors and uses thereof
JP7670481B2 (ja) 2017-08-04 2025-04-30 バイスクルテクス・リミテッド Ｃｄ１３７に対して特異的な二環式ペプチドリガンド
EP3668887A1 (fr) 2017-08-14 2020-06-24 Bicyclerd Limited Conjugués ligands peptidiques bicycliques et leurs utilisations
EP3668550A1 (fr) 2017-08-14 2020-06-24 Bicyclerd Limited Conjugués peptide bicyclique-ligand ppr-a et leurs utilisations
EP3675838A4 (fr) 2017-08-29 2021-04-21 PureTech LYT, Inc. Promédicaments lipidiques orientant vers le système lymphatique
US11883497B2 (en) 2017-08-29 2024-01-30 Puretech Lyt, Inc. Lymphatic system-directing lipid prodrugs
WO2019060693A1 (fr) 2017-09-22 2019-03-28 Kymera Therapeutics, Inc. Ligands crbn et utilisations de ces derniers
CA3076613A1 (fr) 2017-09-22 2019-03-28 Kymera Therapeutics, Inc. Agents de degradation des proteines et utilisations de ces derniers
MY208007A (en) 2017-09-27 2025-04-04 Incyte Corp Salts of pyrrolotriazine derivatives useful as tam inhibitors
CN109651424B (zh) * 2017-10-11 2021-01-22 新发药业有限公司 一种7-保护基-4-(1-氢-吡唑-4-基)吡咯[2,3-d]嘧啶的合成方法
US10800775B2 (en) 2017-11-03 2020-10-13 Aclaris Therapeutics, Inc. Pyrazolyl pyrrolo[2,3-b]pyrmidine-5-carboxylate analogs and methods of making the same
BR112020008850A2 (pt) 2017-11-03 2020-10-20 Aclaris Therapeutics, Inc. composto, composição farmacêutica e método para tratar uma doença mediada por jak1 e jak3
KR102034538B1 (ko) 2017-11-28 2019-10-21 주식회사한국파마 Jak 저해제 화합물, 및 이의 제조방법
WO2019113487A1 (fr) 2017-12-08 2019-06-13 Incyte Corporation Polythérapie à faible dose pour le traitement de néoplasmes myéloprolifératifs
US11304954B2 (en) 2017-12-19 2022-04-19 Puretech Lyt, Inc. Lipid prodrugs of mycophenolic acid and uses thereof
EP3727362A4 (fr) 2017-12-19 2021-10-06 PureTech LYT, Inc. Promédicaments lipidiques d'acide mycophénolique et leurs utilisations
TWI825046B (zh) 2017-12-19 2023-12-11 英商拜西可泰克斯有限公司 Epha2特用之雙環胜肽配位基
US11608345B1 (en) 2017-12-19 2023-03-21 Puretech Lyt, Inc. Lipid prodrugs of rapamycin and its analogs and uses thereof
GB201721265D0 (en) 2017-12-19 2018-01-31 Bicyclerd Ltd Bicyclic peptide ligands specific for EphA2
IL315310A (en) 2017-12-26 2024-10-01 Kymera Therapeutics Inc Irak degraders and uses thereof
EP3737675A4 (fr) 2018-01-12 2022-01-05 Kymera Therapeutics, Inc. Ligands crbn et leurs utilisations
US11485743B2 (en) 2018-01-12 2022-11-01 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US12398209B2 (en) 2018-01-22 2025-08-26 Janssen Biotech, Inc. Methods of treating cancers with antagonistic anti-PD-1 antibodies
EP3746075B1 (fr) 2018-01-29 2025-09-03 Merck Patent GmbH Inhibiteurs de gcn2 et leurs utilisations
IL312674A (en) 2018-01-29 2024-07-01 Merck Patent Gmbh GCN2 inhibitors and uses thereof
CN112105608B (zh) 2018-01-30 2023-07-14 因赛特公司 制备(1-(3-氟-2-(三氟甲基)异烟碱基)哌啶-4-酮)的方法
BR112020016628A2 (pt) 2018-02-16 2020-12-15 Incyte Corporation Inibidores da via de jak1 para o tratamento de distúrbios relacionados a citocinas
JP2021514953A (ja) 2018-02-23 2021-06-17 バイスクルテクス・リミテッド 多量体二環式ペプチドリガンド
CA3091142C (fr) 2018-02-26 2023-04-11 Gilead Sciences, Inc. Composes de pyrrolizine substitues et utilisations connexes
CN117304157A (zh) 2018-02-27 2023-12-29 阿塔克斯生物制药有限公司 作为tcr-nck相互作用的抑制剂的色烯衍生物
MX2020009305A (es) 2018-03-08 2020-11-24 Novartis Ag Uso de un anticuerpo anti-p-selectina.
CN110357887B (zh) * 2018-03-26 2022-09-16 武汉誉祥医药科技有限公司 取代的7H-吡咯并[2,3-d]嘧啶衍生物及其制备方法和用途
SMT202400306T1 (it) 2018-03-30 2024-09-16 Incyte Corp Trattamento dell'idrosadenite suppurativa utilizzando inibitori di jak.
WO2019191679A1 (fr) 2018-03-30 2019-10-03 Incyte Corporation Biomarqueurs pour maladie cutanée inflammatoire
SG11202010092XA (en) 2018-04-13 2020-11-27 Incyte Corp Biomarkers for graft-versus-host disease
EP3784669B1 (fr) 2018-04-24 2023-10-25 Vertex Pharmaceuticals Incorporated Composés de ptéridinone et leurs utilisations
PT3784666T (pt) 2018-04-24 2022-06-06 Merck Patent Gmbh Compostos antiproliferação e utilizações dos mesmos
TWI869346B (zh) 2018-05-30 2025-01-11 瑞士商諾華公司 Ｅｎｔｐｄ２抗體、組合療法、及使用該等抗體和組合療法之方法
WO2019232244A2 (fr) 2018-05-31 2019-12-05 Novartis Ag Molécules d'anticorps anti-cd73 et leurs utilisations
AU2019277560B2 (en) 2018-06-01 2025-04-24 Incyte Corporation Dosing regimen for the treatment of PI3K related disorders
JP7083203B2 (ja) 2018-06-06 2022-06-10 ジェングル セラピューティクス，インコーポレイテッド ピラゾロピリミジン誘導体、その用途並びに医薬組成物
IL279329B2 (en) 2018-06-15 2025-01-01 Navitor Pharm Inc Rapamycin analogs and their uses
US11180531B2 (en) 2018-06-22 2021-11-23 Bicycletx Limited Bicyclic peptide ligands specific for Nectin-4
GB201810316D0 (en) 2018-06-22 2018-08-08 Bicyclerd Ltd Peptide ligands for binding to EphA2
AR117600A1 (es) 2018-06-29 2021-08-18 Incyte Corp Formulaciones de un inhibidor de axl / mer
JP6830460B2 (ja) * 2018-07-05 2021-02-17 コンサート ファーマシューティカルズ インコーポレイテッド ルキソリチニブの重水素化誘導体
WO2020010227A1 (fr) 2018-07-06 2020-01-09 Kymera Therapeutics, Inc. Agents de dégradation de protéines et leurs utilisations
US11292792B2 (en) 2018-07-06 2022-04-05 Kymera Therapeutics, Inc. Tricyclic CRBN ligands and uses thereof
KR102653681B1 (ko) 2018-07-31 2024-04-03 록쏘 온콜로지, 인코포레이티드 (s)-5-아미노-3-(4-((5-플루오로-2-메톡시벤즈아미도)메틸)페닐)-1-(1,1,1-트리플루오로프로판-2-일)-1h-피라졸-4-카르복스아미드의분무-건조된 분산물 및 제제
EP3833350A4 (fr) 2018-08-10 2022-05-18 Aclaris Therapeutics, Inc. Inhibiteurs de pyrrolopyrimidine itk
WO2020039401A1 (fr) 2018-08-24 2020-02-27 Novartis Ag Traitement comprenant des anticorps se liant à il-1 βeta et ses combinaisons
US10548889B1 (en) 2018-08-31 2020-02-04 X4 Pharmaceuticals, Inc. Compositions of CXCR4 inhibitors and methods of preparation and use
EP3846793B1 (fr) 2018-09-07 2024-01-24 PIC Therapeutics, Inc. Inhibiteurs d'eif4e et leurs utilisations
US11414431B2 (en) 2018-10-15 2022-08-16 Nimbus Lakshmi, Inc. Substituted pyrazolo[1,5-a]pyrimidines as TYK2 inhibitors
WO2020084305A1 (fr) 2018-10-23 2020-04-30 Bicycletx Limited Ligands peptidiques bicycliques et leurs utilisations
EP3870158A4 (fr) 2018-10-24 2022-08-10 Navitor Pharmaceuticals, Inc. Composés polymorphes et leurs utilisations
CN113490484B (zh) 2018-10-31 2024-08-23 因赛特公司 治疗血液疾病的组合疗法
JP7623943B2 (ja) 2018-11-30 2025-01-29 カイメラ セラピューティクス， インコーポレイテッド Ｉｒａｋ分解剤およびそれらの使用
CN113271938A (zh) 2018-11-30 2021-08-17 林伯士拉克许米公司 Tyk2抑制剂和其用途
CN109394768B (zh) * 2018-12-10 2019-08-23 牡丹江医学院 一种治疗湿疹的药物及其制备方法
GB201820295D0 (en) 2018-12-13 2019-01-30 Bicyclerd Ltd Bicyclic peptide ligands specific for MT1-MMP
GB201820325D0 (en) 2018-12-13 2019-01-30 Bicyclerd Ltd Bicyclic peptide ligands specific for psma
GB201820288D0 (en) 2018-12-13 2019-01-30 Bicycle Tx Ltd Bicycle peptide ligaands specific for MT1-MMP
CN111320633B (zh) * 2018-12-14 2022-09-27 中国医药研究开发中心有限公司 吡咯/咪唑并六元杂芳环类化合物及其制备方法和医药用途
EP3898626A1 (fr) 2018-12-19 2021-10-27 Array Biopharma, Inc. Composés pyrazolo[1,5-a]pyridine substitués servant d'inhibiteurs de tyrosine kinases fgfr
WO2020131674A1 (fr) 2018-12-19 2020-06-25 Array Biopharma Inc. Dérivés de 7-((3,5-diméthoxyphényl)amino)quinoxaline servant d'inhibiteurs de fgfr pour le traitement du cancer
EP3670659A1 (fr) 2018-12-20 2020-06-24 Abivax Biomarqueurs et leurs utilisations dans le traitement d'infections virales, d'inflammations ou du cancer
CN113195000A (zh) 2018-12-21 2021-07-30 第一三共株式会社 抗体-药物缀合物和激酶抑制剂的组合
EP3897849A1 (fr) 2018-12-21 2021-10-27 BicycleTx Limited Ligands peptidiques bicycliques spécifiques pour pd-l1
CA3126034A1 (fr) 2019-01-23 2020-07-30 Nimbus Lakshmi, Inc. Inhibiteurs de tyk2 et leurs utilisations
WO2020165600A1 (fr) 2019-02-14 2020-08-20 Bicycletx Limited Conjugués peptide-ligand bicyclique et leurs utilisations
CN111620873B (zh) * 2019-02-28 2021-12-28 沈阳药科大学 一类含哌啶的吡咯并[2,3-d]嘧啶衍生物及其制备和用途
JP2022524997A (ja) 2019-03-05 2022-05-11 インサイト・コーポレイション 慢性肺同種移植片機能不全の治療のためのｊａｋ１経路阻害剤
CN113811305A (zh) 2019-03-11 2021-12-17 诺西恩医疗公司 带电的离子通道阻滞剂及其使用方法
SG11202109713PA (en) 2019-03-11 2021-10-28 Nocion Therapeutics Inc Ester substituted ion channel blockers and methods for use
IL286172B1 (en) 2019-03-11 2025-10-01 Nocion Therapeutics Inc Charged ion channel blockers and methods of use
US10786485B1 (en) 2019-03-11 2020-09-29 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10780083B1 (en) 2019-03-11 2020-09-22 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11624751B2 (en) 2019-03-19 2023-04-11 Incyte Corporation Biomarkers for vitiligo
KR20210142154A (ko) 2019-03-21 2021-11-24 옹쎄오 암 치료를 위한 키나제 억제제와 조합된 dbait 분자
EP3946462A1 (fr) 2019-04-02 2022-02-09 BicycleTX Limited Conjugués de toxines bicycliques et leurs utilisations
MX2021012216A (es) 2019-04-05 2022-01-24 Kymera Therapeutics Inc Degradadores de transductores de señal y activadores de transcripción (stat) y usos de los mismos.
EP3958968A1 (fr) 2019-04-24 2022-03-02 Elanco Us Inc. Inhibiteur de jak 7h-pyrrolo[2,3-d]pyrimidine
KR20220004726A (ko) 2019-05-02 2022-01-11 어클라리스 쎄라퓨틱스, 인코포레이티드 Jak 억제제로서의 치환된 피롤로피리딘
CN110028509B (zh) * 2019-05-27 2020-10-09 上海勋和医药科技有限公司 作为选择性jak2抑制剂的吡咯并嘧啶类化合物、其合成方法及用途
KR102286372B1 (ko) 2019-05-27 2021-08-05 주식회사한국파마 Jak 저해제 화합물, 및 이를 포함하는 의약 조성물
JP7592029B2 (ja) * 2019-05-28 2024-11-29 マンカインド ファーマ リミテッド ヤヌスキナーゼ１の阻害のための新規化合物
CA3141826A1 (fr) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2020252012A1 (fr) * 2019-06-10 2020-12-17 Incyte Corporation Traitement topique du vitiligo par un inhibiteur de jak
MX2022000016A (es) 2019-06-27 2022-02-24 Crispr Therapeutics Ag Uso de linfocitos t con receptor de antigeno quimerico e inhibidores de linfocitos citoliticos naturales para el tratamiento del cancer.
CN110305140B (zh) 2019-07-30 2020-08-04 上海勋和医药科技有限公司 二氢吡咯并嘧啶类选择性jak2抑制剂
TWI860386B (zh) 2019-07-30 2024-11-01 英商拜西可泰克斯有限公司 異質雙環肽複合物
WO2021022178A1 (fr) * 2019-07-31 2021-02-04 Aclaris Therapeutics, Inc. Pyrrolopyridines de sulfonamide substituées servant d'inhibiteurs de jak
US20220251097A1 (en) * 2019-08-01 2022-08-11 St. Jude Childrens's Research Hospital Molecules and methods related to treatment of uncontrolled cellular proliferation
US11845724B2 (en) 2019-09-11 2023-12-19 Vincere Biosciences, Inc. USP30 inhibitors and uses thereof
US12215105B2 (en) 2019-09-13 2025-02-04 Nimbus Saturn, Inc. HPK1 antagonists and uses thereof
WO2021053490A1 (fr) 2019-09-16 2021-03-25 Novartis Ag Utilisation d'un anticorps anti-igg4 à domaine 3 de mucine (tim-3) et à domaine d'immunoglobuline des lymphocytes t humanisés, de blocage de ligands, à haute affinité pour le traitement de la myélofibrose
KR20220063215A (ko) 2019-09-16 2022-05-17 노파르티스 아게 골수섬유증의 치료를 위한 mdm2 억제제의 용도
CN114502590A (zh) 2019-09-18 2022-05-13 诺华股份有限公司 Entpd2抗体、组合疗法、以及使用这些抗体和组合疗法的方法
CN114761013A (zh) 2019-09-27 2022-07-15 迪斯克医药公司 治疗骨髓纤维化和相关病症的方法
CN110538183B (zh) * 2019-10-09 2021-05-04 吉林大学 一种预防和治疗小儿湿疹的组合物及其制备方法
CA3157499A1 (fr) 2019-10-10 2021-04-15 Incyte Corporation Biomarqueurs de la maladie du greffon contre l'hote
US12360120B2 (en) 2019-10-10 2025-07-15 Incyte Corporation Biomarkers for graft-versus-host disease
JP7518900B2 (ja) 2019-10-16 2024-07-18 インサイト・コーポレイション 皮膚エリテマトーデス及び扁平苔癬（ｌｐ）の治療のためのｊａｋ１阻害剤の使用
US11992490B2 (en) 2019-10-16 2024-05-28 Incyte Corporation Use of JAK1 inhibitors for the treatment of cutaneous lupus erythematosus and Lichen planus (LP)
WO2021087432A1 (fr) 2019-11-01 2021-05-06 Navitor Pharmaceuticals, Inc. Méthodes de traitement à l'aide d'un modulateur de mtorc1
CA3155568A1 (fr) 2019-11-06 2021-05-14 Bridget Mccarthy Cole Bloqueurs de canaux ioniques charges et leurs procedes d'utilisation
IL292505A (en) 2019-11-06 2022-06-01 Nocion Therapeutics Inc Charged ion channel blockers and methods of use
CN114761006A (zh) 2019-11-08 2022-07-15 Inserm(法国国家健康医学研究院) 对激酶抑制剂产生耐药性的癌症的治疗方法
KR20220107213A (ko) 2019-11-22 2022-08-02 인사이트 코포레이션 Alk2 억제제 및 jak2 억제제를 포함하는 병용 요법
JP2023506410A (ja) 2019-12-05 2023-02-16 アナクリア セラピューティクス， インコーポレイテッド ラパマイシン類似体及びその使用
US11591332B2 (en) 2019-12-17 2023-02-28 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
KR20220145325A (ko) 2019-12-17 2022-10-28 카이메라 쎄라퓨틱스 인코포레이티드 Irak 분해제 및 이의 용도
WO2021133920A1 (fr) 2019-12-23 2021-07-01 Kymera Therapeutics, Inc. Agents de dégradation de smarca et leurs utilisations
AU2020417293A1 (en) 2020-01-03 2022-09-01 Berg Llc Polycyclic amides as UBE2K modulators for treating cancer
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
CN115348864A (zh) 2020-02-05 2022-11-15 纯技术Lyt股份有限公司 神经甾体的脂质前药
CN111728975A (zh) * 2020-02-25 2020-10-02 广东省检迅检测科技有限公司 用于减少运动损伤和促进运动损伤修复的组合物
US11753403B2 (en) 2020-03-03 2023-09-12 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof
EP4114401A1 (fr) 2020-03-06 2023-01-11 Incyte Corporation Polythérapie comprenant des inhibiteurs d'axl/mer et de pd-1/pd-l1
WO2021183639A1 (fr) 2020-03-11 2021-09-16 Nocion Therapeutics, Inc. Bloqueurs de canaux ioniques chargés et leurs procédés d'utilisation
US12162851B2 (en) 2020-03-11 2024-12-10 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
WO2021188948A1 (fr) 2020-03-19 2021-09-23 Kymera Therapeutics, Inc. Agents de dégradation de mdm2 et leurs utilisations
US11324750B2 (en) 2020-04-09 2022-05-10 Children's Hospital Medical Center Compositions and methods for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
EP3892280A3 (fr) 2020-04-09 2022-01-12 Children's Hospital Medical Center Biomarqueurs d'une infection sars-cov-2 et leurs utilisations
WO2021206766A1 (fr) 2020-04-09 2021-10-14 Children's Hospital Medical Center Biomarqueurs d'infection par sras-cov-2 et leurs utilisations
US20230218644A1 (en) 2020-04-16 2023-07-13 Som Innovation Biotech, S.A. Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus
KR20230012539A (ko) 2020-05-13 2023-01-26 디스크 메디슨, 인크. 골수섬유증을 치료하기 위한 항-헤모주벨린 (hjv) 항체
WO2021236139A1 (fr) 2020-05-21 2021-11-25 Concert Pharmaceuticals, Inc. Nouvel inhibiteur de jak deutéré et ses utilisations
US11685731B2 (en) 2020-06-02 2023-06-27 Incyte Corporation Processes of preparing a JAK1 inhibitor
WO2021247897A1 (fr) 2020-06-03 2021-12-09 Kymera Therapeutics, Inc. Agents de dégradation d'irak deutérés et leurs utilisations
CA3184633A1 (fr) 2020-06-03 2021-12-09 Incyte Corporation Polytherapie pour le traitement des neoplasies myeloproliferatives
TW202210483A (zh) 2020-06-03 2022-03-16 美商凱麥拉醫療公司 Irak降解劑之結晶型
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
CN116057045A (zh) 2020-06-05 2023-05-02 金耐特生物制药公司 成纤维细胞生长因子受体激酶抑制剂
EP4171585A1 (fr) 2020-06-26 2023-05-03 CRISPR Therapeutics AG Thérapie cellulaire allogénique de malignités de lymphocytes b à l'aide de lymphocytes t génétiquement modifiés ciblant cd19
EP3944859A1 (fr) 2020-07-30 2022-02-02 Assistance Publique Hôpitaux de Paris Procédé de traitement des toxicités immunitaires induites par des inhibiteurs des points de contrôle immunitaire
US11751108B2 (en) * 2020-08-05 2023-09-05 Qualcomm Incorporated Execution of reduced signaling handover
CN116348467A (zh) * 2020-08-12 2023-06-27 康塞特医药品有限公司 用于制备对映异构体富集的jak抑制剂的方法
KR20230074721A (ko) 2020-08-17 2023-05-31 바이사이클티엑스 리미티드 Nectin-4에 특이적인 이환 콘쥬게이트 및 이의 용도
CA3192099A1 (fr) 2020-08-18 2022-02-24 Incyte Corporation Procede et intermediaires pour la preparation d'un inhibiteur de jak
WO2022040172A1 (fr) 2020-08-18 2022-02-24 Incyte Corporation Procédé et intermédiaires pour la préparation d'un inhibiteur de jak1
JP2023541052A (ja) * 2020-09-16 2023-09-27 エクセソ バイオファーマ カンパニー リミテッド ピリミドピリミジノン化合物及びそれを含む薬剤学的組成物
CN116261447A (zh) 2020-09-16 2023-06-13 因赛特公司 局部治疗白癜风
CA3197645A1 (fr) 2020-10-02 2022-04-07 Incyte Corporation Ruxolitinib topique pour le traitement de lichen plan
TW202227076A (zh) 2020-10-08 2022-07-16 瑞士商諾華公司 Ｅｒｋ抑制劑用於治療骨髓纖維化之用途
EP4225317A1 (fr) 2020-10-08 2023-08-16 Novartis AG Utilisation d'un inhibiteur d'erk pour le traitement de la myélofibrose
JP2023546996A (ja) 2020-10-23 2023-11-08 ニンバス クロソー， インコーポレイテッド Ｃｔｐｓ１阻害剤およびその使用
CN114437079B (zh) * 2020-10-30 2024-11-01 杭州邦顺制药有限公司 吡咯嘧啶五元氮杂环化合物的晶型
KR102551758B1 (ko) 2020-11-30 2023-07-05 주식회사한국파마 신규한 jak 특이 저해제 화합물, 및 이의 제조방법
EP4255895A1 (fr) 2020-12-02 2023-10-11 Ikena Oncology, Inc. Inhibiteurs de tead et utilisations associées
WO2022120353A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
KR20230128472A (ko) 2020-12-04 2023-09-05 인사이트 코포레이션 피부 질환의 치료를 위한 비타민 d 유사체를 함유하는jak 억제제
CA3204374A1 (fr) 2020-12-08 2022-06-16 Incyte Corporation Inhibiteurs de la voie jak1 destines au traitement du vitiligo
JP2023554665A (ja) 2020-12-18 2023-12-28 ベーリンガー インゲルハイム アニマル ヘルス ユーエスエイ インコーポレイテッド ホウ素含有ピラゾール化合物、それらを含む組成物、それらの方法及び使用
AR124547A1 (es) 2020-12-30 2023-04-05 Kymera Therapeutics Inc Degradadores de irak y sus usos
TW202237083A (zh) 2021-01-11 2022-10-01 美商英塞特公司 包含ｊａｋ路徑抑制劑及ｒｏｃｋ抑制劑之組合療法
WO2022165530A1 (fr) * 2021-02-01 2022-08-04 Janssen Biotech, Inc. Inhibiteurs à petites molécules de kinases inductibles par le sel
BR112023015590A2 (pt) 2021-02-02 2023-10-17 Liminal Biosciences Ltd Antagonistas de gpr84 e usos dos mesmos
US12378229B2 (en) 2021-02-02 2025-08-05 Liminal Biosciences Limited GPR84 antagonists and uses thereof
WO2022166796A1 (fr) * 2021-02-05 2022-08-11 上海齐鲁制药研究中心有限公司 Inhibiteur du récepteur de l'adénosine hétérocyclique de type pyrimidine ou pyridine, son procédé de préparation et son utilisation
WO2022174253A1 (fr) 2021-02-12 2022-08-18 Nimbus Saturn, Inc. Antagonistes de hpk1 et leurs utilisations
MX2023009527A (es) 2021-02-15 2023-08-24 Kymera Therapeutics Inc Degradadores de la cinasa 4 asociada al receptor de interleucina 1 (irak4) y usos de los mismos.
US11773103B2 (en) 2021-02-15 2023-10-03 Kymera Therapeutics, Inc. IRAK4 degraders and uses thereof
CA3206708A1 (fr) 2021-02-25 2022-09-01 Ida ARONCHIK Utilisation d'un inhibiteur de bet seul ou en combinaison avec du fedratinib ou du ruxolitinib pour le traitement d'une malignite hematologique telle que la myelofibrose
EP4301756A4 (fr) 2021-03-05 2025-02-26 Nimbus Saturn, Inc. Antagonistes de hpk1 et leurs utilisations
US12071442B2 (en) 2021-03-29 2024-08-27 Nimbus Saturn, Inc. Substituted pyrrolo[3,4-c]pyridines as HPK1 antagonists
BR112023020781A2 (pt) 2021-04-09 2023-12-19 Nimbus Clio Inc Moduladores de cbl-b e usos dos mesmos
EP4323066A1 (fr) 2021-04-16 2024-02-21 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
MX2023013052A (es) 2021-05-03 2024-01-12 Incyte Corp Inhibidores de la via de la cinasa jano 1 (jak1) para el tratamiento del prurigo nodularis.
AR125798A1 (es) 2021-05-07 2023-08-16 Kymera Therapeutics Inc Degradadores cdk2 y usos de los mismos
JP2024526762A (ja) 2021-07-12 2024-07-19 インサイト・コーポレイション Ｊａｋ阻害剤を調製するためのプロセス及び中間体
WO2023018904A1 (fr) 2021-08-11 2023-02-16 Concert Pharmaceuticals, Inc. Traitement des troubles de la chute des cheveux par des inhibiteurs de jak deutérés
CA3229560A1 (fr) 2021-08-25 2023-03-02 Christopher L. Vandeusen Inhibiteurs d'eif4e et leurs utilisations
JP2024532276A (ja) 2021-08-25 2024-09-05 ピク セラピューティクス， インコーポレイテッド ｅＩＦ４Ｅ阻害剤及びその使用
KR102718345B1 (ko) * 2021-09-16 2024-10-17 광주과학기술원 신규한 트리아졸릴피롤로피리미딘 유도체 및 이의 용도
WO2023042224A1 (fr) * 2021-09-18 2023-03-23 Natco Pharma Limited Procédé amélioré pour la préparation de phosphate de ruxolitinib
US20250051338A1 (en) 2021-10-25 2025-02-13 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof
EP4422635A4 (fr) 2021-10-29 2025-11-26 Kymera Therapeutics Inc Agents de dégradation d'irak4 et leur synthèse
CN118696059A (zh) 2021-11-17 2024-09-24 美国全心医药生技股份有限公司 使用抗psgl-1抗体与jak抑制剂的组合治疗t细胞介导的炎症性疾病或癌症的方法
WO2023102559A1 (fr) 2021-12-03 2023-06-08 Incyte Corporation Formulations topiques de ruxolitinib avec un agent d'ajustement du ph à base d'amine organique pour le traitement de maladies de la peau
WO2023114984A1 (fr) 2021-12-17 2023-06-22 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
CN114044777B (zh) * 2022-01-10 2022-04-19 南京佰麦生物技术有限公司 一种磷酸芦可替尼的制备方法
CA3243560A1 (fr) 2022-01-31 2023-08-03 Kymera Therapeutics, Inc. Agents de dégradation d'irak et leurs utilisations
CN114456181A (zh) * 2022-02-21 2022-05-10 浙江乐普药业股份有限公司 一种芦可替尼的制备方法
WO2023173053A1 (fr) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
WO2023173057A1 (fr) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
WO2023211889A1 (fr) 2022-04-25 2023-11-02 Ikena Oncology, Inc. Composés polymorphes et leurs utilisations
IL316768A (en) 2022-05-25 2025-01-01 Ikena Oncology Inc MEK inhibitors and their uses
JP2025519705A (ja) * 2022-06-14 2025-06-26 インサイト・コーポレイション Ｊａｋ阻害剤の固体形態及びその調製プロセス
CN117384163A (zh) * 2022-07-05 2024-01-12 盛世泰科生物医药技术(苏州)股份有限公司 一种含偕二氟基的化合物及其制备方法和用途
IL318575A (en) 2022-08-02 2025-03-01 Liminal Biosciences Ltd HETEROARYL CARBOXAMIDE AND GPR84-RELATED ANTAGONISTS AND USES THEREOF
IL318577A (en) 2022-08-02 2025-03-01 Liminal Biosciences Ltd ARYL-TRIAZOLYL AND RELATED GPR84 ANTAGONISTS AND THEIR USES
JP2025527248A (ja) 2022-08-02 2025-08-20 リミナル・バイオサイエンシーズ・リミテッド 置換ピリドンｇｐｒ８４アンタゴニスト及びその使用
AU2023318885A1 (en) 2022-08-03 2025-02-13 Medichem, S.A. Stable oral pharmaceutical formulation containing ruxolitinib hemifumarate
US20250215003A1 (en) * 2022-08-22 2025-07-03 Granules India Limited An improved process for the preparation of ruxolitinib
WO2024099396A1 (fr) * 2022-11-11 2024-05-16 浙江奥翔药业股份有限公司 Cristal de ruxolitinib et composition pharmaceutique de celui-ci
AR131141A1 (es) 2022-11-22 2025-02-19 Pic Therapeutics Inc Inhibidores de eif4e y usos de los mismos
WO2024184926A1 (fr) * 2023-03-08 2024-09-12 Aarti Pharmalabs Limited Procédé de préparation de ruxolitinib chiral et de sels de celui-ci
WO2024187415A1 (fr) * 2023-03-15 2024-09-19 Zhejiang Qizheng Pharmaceutical Co., Ltd. Composition pharmaceutique comprenant du ruxolitinib
WO2024187416A1 (fr) * 2023-03-15 2024-09-19 Zhejiang Qizheng Pharmaceutical Co., Ltd. Composition pharmaceutique comprenant du ruxolitinib
US20240398810A1 (en) 2023-05-21 2024-12-05 Incyte Corporation Topical ruxolitinib foam
EP4620470A3 (fr) 2023-06-23 2025-10-08 Kymera Therapeutics, Inc. Agents de dégradation d'irak et leurs utilisations
EP4491175A1 (fr) 2023-07-10 2025-01-15 Genepharm S.A. Composition orale solide de ruxolitinib
AU2024335978A1 (en) 2023-09-04 2025-10-30 Granules India Limited Improved process for the preparation of ruxolitinib and novel crystalline form thereof
IT202300018879A1 (it) 2023-09-14 2025-03-14 Chemelectiva S R L Processo enzimatico per la preparazione di (r)-3-(4-bromo-1h-pirazol-1-il)-3- ciclopentilpropanenitrile, quale intermedio nella sintesi di ruxolitinib
WO2025062372A1 (fr) 2023-09-21 2025-03-27 Takeda Pharmaceutical Company Limited Inhibiteurs de tyk2 destinés à être utilisés dans le traitement d'une maladie inflammatoire de l'intestin
US12364699B2 (en) 2023-10-10 2025-07-22 Sun Pharmaceuticals Industries, Inc. Method of treating hair loss disorders
WO2025117642A1 (fr) 2023-12-01 2025-06-05 Incyte Corporation Ruxolitinib pour le traitement de l'hidrosadénite suppurée (hs)
EP4621803A1 (fr) 2024-03-22 2025-09-24 Assistance Publique - Hôpitaux de Paris Procédé d'identification de patients nécessitant un traitement de myotoxicité induite par l'ici
WO2025207818A1 (fr) * 2024-03-27 2025-10-02 Gilead Sciences, Inc. Modulateurs à petites molécules de stat6
US20250325664A1 (en) 2024-04-22 2025-10-23 Incyte Corporation Combination therapy with an anti-colony stimulating factor 1 receptor antibody and a jak inhibitor

Family Cites Families (311)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2985589A (en) 1957-05-22 1961-05-23 Universal Oil Prod Co Continuous sorption process employing fixed bed of sorbent and moving inlets and outlets
US3632836A (en) 1968-10-25 1972-01-04 Dow Chemical Co Solid curable polyepoxides modified with hydrolyzed liquid polyepoxides
US3832460A (en) 1971-03-19 1974-08-27 C Kosti Anesthetic-vasoconstrictor-antihistamine composition for the treatment of hypertrophied oral tissue
US4140755A (en) * 1976-02-13 1979-02-20 Hoffmann-La Roche Inc. Sustained release tablet formulations
DE3036390A1 (de) 1980-09-26 1982-05-13 Troponwerke GmbH & Co KG, 5000 Köln Neue pyrrolo-pyrimidine, verfahren zu ihrer herstellung und ihre verwendung bei der herstellung von biologischen wirkstoffen
DE3220113A1 (de) 1982-05-28 1983-12-01 Basf Ag, 6700 Ludwigshafen Difluormethoxiphenylthiophosphorsaeureester
US4402832A (en) 1982-08-12 1983-09-06 Uop Inc. High efficiency continuous separation process
US4404335A (en) 1982-08-16 1983-09-13 The Dow Chemical Company Hydrolyzing epoxy resins in absence of solvent and in presence of oxalic acid and a phosphonium compound
US4548990A (en) 1983-08-15 1985-10-22 Ciba-Geigy Corporation Crosslinked, porous polymers for controlled drug delivery
US4498991A (en) 1984-06-18 1985-02-12 Uop Inc. Serial flow continuous separation process
NL8403224A (nl) 1984-10-24 1986-05-16 Oce Andeno Bv Dioxafosforinanen, de bereiding ervan en de toepassing voor het splitsen van optisch actieve verbindingen.
CA1306260C (fr) 1985-10-18 1992-08-11 Shionogi & Co., Ltd. Derives imidazopyridine condenses
US4921947A (en) 1986-03-31 1990-05-01 Eli Lilly And Company Process for preparing macrolide derivatives
JPH0710876Y2 (ja) 1989-08-31 1995-03-15 石垣機工株式会社 スクリュープレスにおける脱水筒の洗浄装置
ES2087916T3 (es) 1989-10-11 1996-08-01 Teijin Ltd Derivado de pirimidina biciclico, metodo para producir el mismo, y preparacion farmaceutica que contiene el mismo como ingrediente activo.
US5403593A (en) 1991-03-04 1995-04-04 Sandoz Ltd. Melt granulated compositions for preparing sustained release dosage forms
IT1258781B (it) 1992-01-16 1996-02-29 Zambon Spa Composizione farmaceutica oftalmica contenente n-acetilcisteina e polivinilalcol
US5521184A (en) 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
FR2695126B1 (fr) 1992-08-27 1994-11-10 Sanofi Elf Dérivés d'acide thiényl ou pyrrolyl carboxyliques, leur préparation et médicaments les contenant.
AU671491B2 (en) 1992-12-18 1996-08-29 F. Hoffmann-La Roche Ag N-oxycarbonyl substituted 5'-deoxy-5-fluorcytidines
JPH0710876A (ja) * 1993-06-24 1995-01-13 Teijin Ltd ４位に環状アミノ基を有するピロロ［２，３―ｄ］ピリミジン
USH1439H (en) 1993-10-18 1995-05-02 The Dow Chemical Company Method to increase the level of α-glycol in liquid epoxy resin
EP0727217A3 (fr) 1995-02-10 1997-01-15 Suntory Ltd Compositions pharmaceutiques et cosmétiques contenant ellagitannin du type god comme principe actif
IL117580A0 (en) 1995-03-29 1996-07-23 Merck & Co Inc Inhibitors of farnesyl-protein transferase and pharmaceutical compositions containing them
US5856326A (en) 1995-03-29 1999-01-05 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
ES2167586T3 (es) 1995-07-05 2002-05-16 Du Pont Pirimidinonas fungicidas.
JP4146514B2 (ja) 1995-07-06 2008-09-10 ノバルティス アクチエンゲゼルシャフト ピロロピリミジン類およびその製造方法
US5630943A (en) 1995-11-30 1997-05-20 Merck Patent Gesellschaft Mit Beschrankter Haftung Discontinuous countercurrent chromatographic process and apparatus
GB9604361D0 (en) 1996-02-29 1996-05-01 Pharmacia Spa 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors
EP0906099A4 (fr) 1996-04-03 2001-02-07 Merck & Co Inc Methode de traitement du cancer
CA2251955A1 (fr) 1996-04-18 1997-10-23 Nancy E. Kohl Methode de traitement de cancer
US5795909A (en) 1996-05-22 1998-08-18 Neuromedica, Inc. DHA-pharmaceutical agent conjugates of taxanes
JP2000508335A (ja) 1996-05-30 2000-07-04 メルク エンド カンパニー インコーポレーテッド 癌の治療方法
US6624138B1 (en) 2001-09-27 2003-09-23 Gp Medical Drug-loaded biological material chemically treated with genipin
CA2286239A1 (fr) 1997-04-07 1998-10-15 Merck & Co., Inc. Procede de traitement du cancer
US6060038A (en) 1997-05-15 2000-05-09 Merck & Co., Inc. Radiolabeled farnesyl-protein transferase inhibitors
US6063284A (en) 1997-05-15 2000-05-16 Em Industries, Inc. Single column closed-loop recycling with periodic intra-profile injection
EP1001782A4 (fr) 1997-08-11 2002-01-30 Boehringer Ingelheim Pharma 5,6-HETEROARYL-DIPYRIDO 2,3-$i(b):3',2'-$i(f)]AZEPINES ET LEUR UTILISATION DANS LA PREVENTION OU LE TRAITEMENT DE L'INFECTION PAR LE VIH
US7153845B2 (en) 1998-08-25 2006-12-26 Columbia Laboratories, Inc. Bioadhesive progressive hydration tablets
US6075056A (en) 1997-10-03 2000-06-13 Penederm, Inc. Antifungal/steroid topical compositions
SE9800729L (sv) 1998-03-06 1999-09-07 Scotia Lipidteknik Ab Ny topikal formulering I
US6025366A (en) 1998-04-02 2000-02-15 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone
JP2002517396A (ja) 1998-06-04 2002-06-18 アボット・ラボラトリーズ 細胞接着阻害抗炎症性化合物
US6232320B1 (en) 1998-06-04 2001-05-15 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory compounds
PT1087970E (pt) 1998-06-19 2004-06-30 Pfizer Prod Inc Compostos pirrolo¬2,3-d|pirimidina
PA8474101A1 (es) * 1998-06-19 2000-09-29 Pfizer Prod Inc Compuestos de pirrolo [2,3-d] pirimidina
ATE459616T1 (de) 1998-08-11 2010-03-15 Novartis Ag Isochinoline derivate mit angiogenesis-hemmender wirkung
JP2000119271A (ja) 1998-08-12 2000-04-25 Hokuriku Seiyaku Co Ltd １ｈ―イミダゾピリジン誘導体
DK1109534T3 (da) 1998-09-10 2003-06-10 Nycomed Danmark As Farmaceutiske præparater med quick release af den aktive substans
US6413419B1 (en) 1998-10-29 2002-07-02 Institut Francais Du Petrole Process and device for separation with variable-length chromatographic
US6375839B1 (en) 1998-10-29 2002-04-23 Institut Francais Du Petrole Process and device for separation with variable-length chromatographic zones
FR2785196B1 (fr) 1998-10-29 2000-12-15 Inst Francais Du Petrole Procede et dispositif de separation avec des zones chromatographiques a longueur variable
US6133031A (en) 1999-08-19 2000-10-17 Isis Pharmaceuticals Inc. Antisense inhibition of focal adhesion kinase expression
JP2002538121A (ja) 1999-03-03 2002-11-12 メルク エンド カムパニー インコーポレーテッド プレニルタンパク質トランスフェラーゼの阻害剤
GB9905075D0 (en) 1999-03-06 1999-04-28 Zeneca Ltd Chemical compounds
US6217895B1 (en) 1999-03-22 2001-04-17 Control Delivery Systems Method for treating and/or preventing retinal diseases with sustained release corticosteroids
US6239113B1 (en) 1999-03-31 2001-05-29 Insite Vision, Incorporated Topical treatment or prevention of ocular infections
AU3565999A (en) 1999-04-16 2000-11-02 Coelacanth Chemical Corporation Synthesis of azetidine derivatives
US6921763B2 (en) 1999-09-17 2005-07-26 Abbott Laboratories Pyrazolopyrimidines as therapeutic agents
EP1221443B1 (fr) 1999-10-13 2004-09-01 Banyu Pharmaceutical Co., Ltd. Derives d'imidazolidinone a substitution
US7235258B1 (en) 1999-10-19 2007-06-26 Nps Pharmaceuticals, Inc. Sustained-release formulations for treating CNS-mediated disorders
UA72290C2 (uk) * 1999-12-10 2005-02-15 Пфайзер Продактс Інк. СПОЛУКИ ПІРОЛО[2.3-d]ПІРИМІДИНУ, ФАРМАЦЕВТИЧНА КОМПОЗИЦІЯ (ВАРІАНТИ), СПОСІБ ІНГІБУВАННЯ ПРОТЕЇНКІНАЗ АБО JANUS КІНАЗИ 3 (ВАРІАНТИ)
CN1615873A (zh) * 1999-12-24 2005-05-18 阿文蒂斯药物有限公司 氮杂吲哚类化合物
GB0004890D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
US7235551B2 (en) 2000-03-02 2007-06-26 Smithkline Beecham Corporation 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
DK1142566T3 (da) 2000-04-07 2004-02-09 Medidom Lab Oftalmologiske formuleringer på basis af ciclosporin, hyaluronsyre og polysorbat
AU4878601A (en) 2000-04-20 2001-11-07 Mitsubishi Corporation Aromatic amide compounds
EP1278748B1 (fr) * 2000-04-25 2011-03-23 ICOS Corporation Inhibiteurs de la phosphatidyl-inositol 3-kinase delta humaine
CA2412215A1 (fr) 2000-06-16 2001-12-27 Curis, Inc. Compositions modulatrices de l'angiogenese et leurs utilisations
US7498304B2 (en) 2000-06-16 2009-03-03 Curis, Inc. Angiogenesis-modulating compositions and uses
US6335342B1 (en) 2000-06-19 2002-01-01 Pharmacia & Upjohn S.P.A. Azaindole derivatives, process for their preparation, and their use as antitumor agents
JP5000831B2 (ja) 2000-06-23 2012-08-15 田辺三菱製薬株式会社 抗腫瘍作用増強剤
CN100351253C (zh) * 2000-06-26 2007-11-28 辉瑞产品公司 作为免疫抑制剂的吡咯并[2,3－d]嘧啶化合物
JP4188078B2 (ja) 2000-06-28 2008-11-26 スミスクライン ビーチャム ピー エル シー 湿式粉砕法
WO2002016370A1 (fr) 2000-08-22 2002-02-28 Hokuriku Seiyaku Co., Ltd. Derives de 1h-imidazopyridine
US20020111353A1 (en) 2000-12-05 2002-08-15 Mark Ledeboer Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases
GB0100622D0 (en) 2001-01-10 2001-02-21 Vernalis Res Ltd Chemical compounds V111
US20040077654A1 (en) 2001-01-15 2004-04-22 Bouillot Anne Marie Jeanne Aryl piperidine and piperazine derivatives as inducers of ldl-receptor expression
WO2002060492A1 (fr) 2001-01-30 2002-08-08 Cytopia Pty Ltd Procedes d'inhibition de kinases
AU2002308748A1 (en) 2001-05-16 2002-11-25 Vertex Pharmaceuticals Incorporated Heterocyclic substituted pyrazoles as inhibitors of src and other protein kinases
US7301023B2 (en) 2001-05-31 2007-11-27 Pfizer Inc. Chiral salt resolution
GB0115109D0 (en) * 2001-06-21 2001-08-15 Aventis Pharma Ltd Chemical compounds
GB0115393D0 (en) 2001-06-23 2001-08-15 Aventis Pharma Ltd Chemical compounds
WO2003011285A1 (fr) 2001-08-01 2003-02-13 Merck & Co., Inc. Derives de la benzimidazo[4,5-f]isoquinolinone
AU2002337142B2 (en) 2001-09-19 2007-10-11 Aventis Pharma S.A. Indolizines as kinase protein inhibitors
US6429231B1 (en) 2001-09-24 2002-08-06 Bradley Pharmaceuticals, Inc. Compositions containing antimicrobials and urea for the treatment of dermatological disorders and methods for their use
EP1441737B1 (fr) 2001-10-30 2006-08-09 Novartis AG Derives de staurosporine inhibiteurs de l'activite tyrosine kinase du recepteur flt3
JP2003155285A (ja) 2001-11-19 2003-05-27 Toray Ind Inc 環状含窒素誘導体
WO2003048111A1 (fr) 2001-11-30 2003-06-12 Teijin Limited Procede pour produire un compose d'acide 5-(3-cyanophenyl)-3-formylbenzoique
GT200200234A (es) 2001-12-06 2003-06-27 Compuestos cristalinos novedosos
US6995144B2 (en) 2002-03-14 2006-02-07 Eisai Co., Ltd. Nitrogen containing heterocyclic compounds and medicines containing the same
WO2003088952A1 (fr) 2002-04-15 2003-10-30 Adams Laboratories, Inc. Liberation reguliere de medicaments combines de guaifenesin
TW200403058A (en) 2002-04-19 2004-03-01 Bristol Myers Squibb Co Heterocyclo inhibitors of potassium channel function
WO2003091246A1 (fr) 2002-04-26 2003-11-06 Vertex Pharmaceuticals Incorporated Derives de pyrrole utilises en tant qu'inhibiteurs de erk2 et leurs utilisations
AU2003241326B2 (en) 2002-05-02 2008-05-01 Merck & Co., Inc. Tyrosine kinase inhibitors
WO2003094888A1 (fr) 2002-05-07 2003-11-20 Control Delivery Systems, Inc. Procedes de fabrication d'un distributeur de medicaments
DE60317198T2 (de) 2002-05-23 2008-12-04 Cytopia Research Pty. Ltd., Richmond Proteinkinaseinhibitoren
PE20040522A1 (es) 2002-05-29 2004-09-28 Novartis Ag Derivados de diarilurea dependientes de la cinasa de proteina
CA2490340A1 (fr) * 2002-06-26 2004-01-08 Idemitsu Kosan Co., Ltd. Copolymere hydrogene, son procede de production et composition d'adhesif thermofusible le contenant
GB0215676D0 (en) 2002-07-05 2002-08-14 Novartis Ag Organic compounds
GB0215844D0 (en) 2002-07-09 2002-08-14 Novartis Ag Organic compounds
EP1541563A4 (fr) 2002-07-10 2007-11-07 Ono Pharmaceutical Co Antagoniste du ccr4 et utilisation medicinale correspondante
KR20050057175A (ko) 2002-09-20 2005-06-16 알콘, 인코퍼레이티드 안구건조증 치료용 사이토카인 합성 저해제의 용도
US20040204404A1 (en) 2002-09-30 2004-10-14 Robert Zelle Human N-type calcium channel blockers
DE60316013T2 (de) 2002-11-04 2008-05-29 Vertex Pharmaceuticals Inc., Cambridge Heteroaryl-pyrimidinderivate als jak-inhibitoren
US8034831B2 (en) 2002-11-06 2011-10-11 Celgene Corporation Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-Dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies
TWI335913B (en) 2002-11-15 2011-01-11 Vertex Pharma Diaminotriazoles useful as inhibitors of protein kinases
US20040099204A1 (en) 2002-11-25 2004-05-27 Nestor John J. Sheet, page, line, position marker
KR20050086784A (ko) 2002-11-26 2005-08-30 화이자 프로덕츠 인크. 이식 거부반응의 치료 방법
UA80767C2 (en) 2002-12-20 2007-10-25 Pfizer Prod Inc Pyrimidine derivatives for the treatment of abnormal cell growth
UY28126A1 (es) 2002-12-24 2004-06-30 Alcon Inc Uso de glucocorticoides selectivos para la superficie ocular en el tratamiento de la sequedad ocular
US7135493B2 (en) 2003-01-13 2006-11-14 Astellas Pharma Inc. HDAC inhibitor
US7167750B2 (en) 2003-02-03 2007-01-23 Enteromedics, Inc. Obesity treatment with electrically induced vagal down regulation
WO2004072063A1 (fr) 2003-02-07 2004-08-26 Vertex Pharmaceuticals Incorporated Pyrroles a substitution heteroaryle servant d'inhibiteurs de proteines kinases
GB0305929D0 (en) 2003-03-14 2003-04-23 Novartis Ag Organic compounds
WO2004092154A1 (fr) 2003-04-03 2004-10-28 Vertex Pharmaceuticals Incorporated Compositions utiles en tant qu'inhibiteurs de proteines kinases
SE0301372D0 (sv) 2003-05-09 2003-05-09 Astrazeneca Ab Novel compounds
SE0301373D0 (sv) 2003-05-09 2003-05-09 Astrazeneca Ab Novel compounds
FR2857454B1 (fr) 2003-07-08 2006-08-11 Aventis Pasteur Dosage des acides techoiques des bacteries gram+
US20050043346A1 (en) * 2003-08-08 2005-02-24 Pharmacia Italia S.P.A. Pyridylpyrrole derivatives active as kinase inhibitors
US8362017B2 (en) 2003-08-29 2013-01-29 Exelixis, Inc. C-kit modulators and methods of use
EP1678147B1 (fr) 2003-09-15 2012-08-08 Lead Discovery Center GmbH Derives d'aminopyrimidine a disubstitution 4,6 actifs sur le plan pharmaceutique en tant que modulateurs des proteine kinases
AR045944A1 (es) 2003-09-24 2005-11-16 Novartis Ag Derivados de isoquinolina 1.4-disustituidas
DE602004030470D1 (de) 2003-10-24 2011-01-20 Santen Pharmaceutical Co Ltd Therapeutisches mittel für keratokonjunktive erkrankungen
US7387793B2 (en) 2003-11-14 2008-06-17 Eurand, Inc. Modified release dosage forms of skeletal muscle relaxants
MY141220A (en) 2003-11-17 2010-03-31 Astrazeneca Ab Pyrazole derivatives as inhibitors of receptor tyrosine kinases
WO2005051393A1 (fr) 2003-11-25 2005-06-09 Pfizer Products Inc. Methode de traitement de l'atherosclerose
CA2549485A1 (fr) 2003-12-17 2005-07-07 Pfizer Products Inc. Methode pour traiter le rejet de greffe
DE602004016211D1 (en) 2003-12-19 2008-10-09 Schering Corp Thiadiazole als cxc- und cc-chemokinrezeptorliganden
ES2527118T3 (es) 2003-12-19 2015-01-20 Plexxikon Inc. Compuestos y procedimientos de desarrollo de moduladores de Ret
AU2004303602C1 (en) 2003-12-23 2009-05-28 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US20050187389A1 (en) * 2004-01-13 2005-08-25 Ambit Biosciences Corporation Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases
CA2559285A1 (fr) 2004-03-18 2005-09-29 Brigham And Women's Hospital, Inc. Traitement des synucleinopathies
PT1730146E (pt) 2004-03-30 2011-07-11 Vertex Pharma Azaindoles úteis como inibidores de jak e outras proteínas quinases
JP5213229B2 (ja) 2004-04-23 2013-06-19 エグゼリクシス， インコーポレイテッド キナーゼ調節因子および使用方法
WO2005105814A1 (fr) 2004-04-28 2005-11-10 Incyte Corporation Inhibiteurs tetracycliques de janus kinases
WO2005105988A2 (fr) 2004-04-28 2005-11-10 Vertex Pharmaceuticals Incorporated Structure cristalline de complexe de domaine jak3 kinase humaine et ses poches de liaison
JP2007536310A (ja) 2004-05-03 2007-12-13 ノバルティス アクチエンゲゼルシャフト Ｓ１ｐ受容体アゴニストおよびｊａｋ３キナーゼ阻害剤を含む、組合せ剤
JP2007537296A (ja) 2004-05-14 2007-12-20 アボット・ラボラトリーズ 治療薬としてのキナーゼ阻害薬
PE20060426A1 (es) 2004-06-02 2006-06-28 Schering Corp DERIVADOS DE ACIDO TARTARICO COMO INHIBIDORES DE MMPs, ADAMs, TACE Y TNF-alfa
TW200610762A (en) 2004-06-10 2006-04-01 Irm Llc Compounds and compositions as protein kinase inhibitors
EP1760071A4 (fr) 2004-06-23 2008-03-05 Ono Pharmaceutical Co Composé ayant une activité de liaison aux récepteurs s1p et utilisation de celui-ci
EP2325184A1 (fr) 2004-06-30 2011-05-25 Vertex Pharmceuticals Incorporated Azaindoles utilés en tant qu'inhibiteurs des proteine kinases
US7138423B2 (en) 2004-07-20 2006-11-21 Bristol-Myers Squibb Company Arylpyrrolidine derivatives as NK-1 /SSRI antagonists
FR2873691B1 (fr) 2004-07-29 2006-10-06 Sanofi Synthelabo Derives d'amino-piperidine, leur preparation et leur application en therapeutique
WO2006013114A1 (fr) 2004-08-06 2006-02-09 Develogen Aktiengesellschaft Utilisation d'un produit proteique timp-2 secrete pour la prevention et le traitement d'affections du pancreas, de l'obesite et/ou du syndrome metabolique
WO2006022459A1 (fr) 2004-08-23 2006-03-02 Mogam Biotechnology Institute Amorce et sonde pour la detection du coronavirus du sras, trousse comprenant l'amorce et/ou la sonde, et procede de detection associe
GB0421525D0 (en) 2004-09-28 2004-10-27 Novartis Ag Inhibitors of protein kineses
US20070054916A1 (en) 2004-10-01 2007-03-08 Amgen Inc. Aryl nitrogen-containing bicyclic compounds and methods of use
JP2008515939A (ja) 2004-10-13 2008-05-15 エフ．ホフマン−ラ ロシュ アーゲー Ｃｄｋ２及び血管形成の阻害剤として、及び乳癌、結腸癌及び前立腺癌の治療に有用な２置換ピラゾロベンゾジアゼピン
MY179032A (en) 2004-10-25 2020-10-26 Cancer Research Tech Ltd Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors
UY29177A1 (es) 2004-10-25 2006-05-31 Astex Therapeutics Ltd Derivados sustituidos de purina, purinona y deazapurina, composiciones que los contienen métodos para su preparación y sus usos
KR20070090172A (ko) 2004-11-04 2007-09-05 버텍스 파마슈티칼스 인코포레이티드 단백질 키나아제의 억제제로서 유용한피라졸로[1,5-ａ]피리미딘
WO2006056399A2 (fr) 2004-11-24 2006-06-01 Novartis Ag Combinaisons d'inhibiteurs de kinase jak
US7517870B2 (en) 2004-12-03 2009-04-14 Fondazione Telethon Use of compounds that interfere with the hedgehog signaling pathway for the manufacture of a medicament for preventing, inhibiting, and/or reversing ocular diseases related with ocular neovascularization
US20060128803A1 (en) 2004-12-14 2006-06-15 Alcon, Inc. Method of treating dry eye disorders using 13(S)-HODE and its analogs
AR054416A1 (es) 2004-12-22 2007-06-27 Incyte Corp Pirrolo [2,3-b]piridin-4-il-aminas y pirrolo [2,3-b]pirimidin-4-il-aminas como inhibidores de las quinasas janus. composiciones farmaceuticas.
TW200635899A (en) 2004-12-22 2006-10-16 Astrazeneca Ab Chemical compounds
EP1844037A1 (fr) 2005-01-20 2007-10-17 Pfizer Limited Composes chimiques
WO2006096270A1 (fr) * 2005-02-03 2006-09-14 Vertex Pharmaceuticals Incorporated Pyrrolopyrimidines utiles en tant qu’inhibiteurs de la protéine kinase
US7683171B2 (en) 2005-02-04 2010-03-23 Bristol-Myers Squibb Company 1H-imidazo[4,5-d]thieno[3,2-b]pyridine based tricyclic compounds and pharmaceutical compositions comprising same
AU2006227790B2 (en) 2005-03-15 2009-09-10 Irm Llc Compounds and compositions as protein kinase inhibitors
KR20080013886A (ko) 2005-04-05 2008-02-13 파마코페이아, 인코포레이티드 면역억제용 퓨린 및 이미다조피리딘 유도체
GB0510139D0 (en) 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds B1
EP1881983B1 (fr) 2005-05-20 2012-01-11 Vertex Pharmaceuticals, Inc. Pyrrolopyridines utiles en tant qu'inhibiteurs de proteines kinases
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
US7491732B2 (en) 2005-06-08 2009-02-17 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
WO2006136823A1 (fr) 2005-06-21 2006-12-28 Astex Therapeutics Limited Amine contenant des heterocycliques comme inhibiteurs des kinases b
UA95244C2 (ru) 2005-06-22 2011-07-25 Плексикон, Инк. Соединения и способ модулирования активности киназ, и показания для их применения
EP2251341A1 (fr) 2005-07-14 2010-11-17 Astellas Pharma Inc. Hétérocycles inhibiteurs de Janus kinase-3
FR2889662B1 (fr) 2005-08-11 2011-01-14 Galderma Res & Dev Emulsion de type huile-dans-eau pour application topique en dermatologie
US20070049591A1 (en) 2005-08-25 2007-03-01 Kalypsys, Inc. Inhibitors of MAPK/Erk Kinase
CA2621261C (fr) 2005-09-22 2014-05-20 Incyte Corporation Inhibiteurs tetracycliques de janus kinases
NZ567133A (en) 2005-09-30 2011-07-29 Vertex Pharma Deazapurines useful as inhibitors of janus kinases
WO2007044894A2 (fr) 2005-10-11 2007-04-19 Chembridge Research Laboratories, Inc. Systemes d'expression de proteines sans cellules et methodes d'utilisation
AU2006300182B2 (en) 2005-10-14 2012-01-19 Sumitomo Chemical Company, Limited Hydrazide compound and pesticidal use of the same
RU2463302C2 (ru) 2005-10-28 2012-10-10 Астразенека Аб Производные 4-(3-аминопиразол)пиримидина для применения в качестве ингибиторов тирозинкиназы для лечения злокачественного новообразования
NZ592990A (en) 2005-11-01 2013-01-25 Targegen Inc Bi-aryl meta-pyrimidine inhibitors of kinases
WO2007062459A1 (fr) 2005-11-29 2007-06-07 Cytopia Research Pty Ltd Inhibiteurs selectifs de la kinase a base d’un squelette de pyridine
US20130137681A1 (en) 2005-12-13 2013-05-30 Incyte Corporation HETEROARYL SUBSTITUTED PYRROLO[2,3-b]PYRIDINES AND PYRROLO[2,3-b]PYRIMIDINES AS JANUS KINASE INHIBITORS
DK3184526T3 (en) 2005-12-13 2019-01-14 Incyte Holdings Corp PYRROLO [2,3-D] PYRIMIDINE DERIVATIVES AS A JANUS-KINASE INHIBITOR
JP2009521504A (ja) 2005-12-22 2009-06-04 スミスクライン・ビーチャム・コーポレイション Ａｋｔ活性阻害剤
MX2008008320A (es) 2005-12-23 2008-09-03 Smithkline Beecham Corp Inhibidores de azaindol de aurora cinasas.
JP4643455B2 (ja) 2006-01-12 2011-03-02 株式会社ユニバーサルエンターテインメント 遊技システム
NZ601687A (en) 2006-01-17 2014-03-28 Vertex Pharma Azaindoles useful as inhibitors of janus kinases
CA2635899A1 (fr) 2006-01-19 2007-07-26 Osi Pharmaceuticals, Inc. Inhibiteurs de kinase heterobicycliques fusionnes
WO2007090141A2 (fr) 2006-02-01 2007-08-09 Smithkline Beecham Corporation Composés chimiques
US7745477B2 (en) 2006-02-07 2010-06-29 Hoffman-La Roche Inc. Heteroaryl and benzyl amide compounds
WO2007097770A1 (fr) 2006-02-24 2007-08-30 Teva Pharmaceutical Industries Ltd. Comprimés de succinate de métoprolol er et méthodes pour leur préparation
AU2007225836A1 (en) 2006-03-10 2007-09-20 Ono Pharmaceutical Co., Ltd. Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient
EP2003132B1 (fr) 2006-04-03 2014-03-05 Astellas Pharma Inc. Dérivés d'oxadiazole en tant qu'agonistes du S1P1
KR20090018895A (ko) 2006-04-05 2009-02-24 버텍스 파마슈티칼스 인코포레이티드 야누스 키나제의 억제제로서 유용한 데아자푸린
US20090124636A1 (en) 2006-04-12 2009-05-14 Pfizer Inc. Chemical compounds
WO2007129195A2 (fr) 2006-05-04 2007-11-15 Pfizer Products Inc. 4-pyrimidine-5-amino-pyrazoles
EP2040704A2 (fr) 2006-05-18 2009-04-01 Bayer Healthcare Ag Compositions pharmaceutiques contenant du implitapide et leurs méthodes d'application
US7691811B2 (en) 2006-05-25 2010-04-06 Bodor Nicholas S Transporter-enhanced corticosteroid activity and methods and compositions for treating dry eye
TWI398252B (zh) 2006-05-26 2013-06-11 Novartis Ag 吡咯并嘧啶化合物及其用途
NZ573174A (en) 2006-06-01 2012-01-12 Msd Consumer Care Inc Sustained release pharmaceutical dosage form containing phenylephrine
US20080021217A1 (en) 2006-07-20 2008-01-24 Allen Borchardt Heterocyclic inhibitors of rho kinase
WO2008013622A2 (fr) 2006-07-27 2008-01-31 E. I. Du Pont De Nemours And Company Amides azocycliques fongicides
US8492378B2 (en) 2006-08-03 2013-07-23 Takeda Pharmaceutical Company Limited GSK-3β inhibitor
EP2061762B1 (fr) 2006-08-16 2011-07-27 Boehringer Ingelheim International GmbH Composes de pyrazine, leur utilisation et procedes de preparation
CA2662091A1 (fr) 2006-09-08 2008-03-13 Novartis Ag Derives du n-biaryl (hetero) arylsulphonamide utilisables pour traiter des maladies induites par des interactions avec les lymphocytes
WO2008035376A2 (fr) 2006-09-19 2008-03-27 Council Of Scientific & Industrial Research Nouvel insert bio-érodable pour applications ophtalmiques et procédé de préparation correspondant
CL2007002867A1 (es) 2006-10-04 2008-06-27 Pharmacopeia Inc Compuestos derivados de 2-(bencimidazolil)purina, inhibidores de janus quinasa 3; composicion farmaceutica que los contiene; y su uso para tratar enfermedades autoinmune, inflamatorias, cardiovasculares, rechazo de implante, entre otras.
WO2008043031A1 (fr) 2006-10-04 2008-04-10 Pharmacopeia, Inc. Dérivés de 2-(benzimidazolyl) purine et de purinone substitués en position 6 pour immunosuppression
US20120225057A1 (en) 2006-10-11 2012-09-06 Deciphera Pharmaceuticals, Llc Methods and compositions for the treatment of myeloproliferative diseases and other proliferative diseases
MX2009004700A (es) 2006-11-06 2009-05-15 Supergen Inc Derivados de imidazo[1,2-b]piridazin y pirazolo[1,5-a] pirimidina y su uso como inhibidores de proteina cinasa.
US20080119496A1 (en) 2006-11-16 2008-05-22 Pharmacopeia Drug Discovery, Inc. 7-Substituted Purine Derivatives for Immunosuppression
MX2009005144A (es) 2006-11-22 2009-05-27 Incyte Corp Imidazotriazinas e imidazopirimidinas como inhibidores de cinasa.
WO2008067119A2 (fr) 2006-11-27 2008-06-05 Smithkline Beecham Corporation Nouveaux composés
EP2109364A4 (fr) 2006-12-15 2010-04-14 Abbott Lab Composés d'oxadiazole innovants
EP2125781A2 (fr) 2006-12-20 2009-12-02 Amgen Inc. Hétérocycles substitués et leurs méthodes d'utilisation
JP5528812B2 (ja) 2006-12-20 2014-06-25 アムジエン・インコーポレーテツド 複素環式化合物ならびに炎症、血管形成および癌の治療におけるこれらの使用
EP2121692B1 (fr) 2006-12-22 2013-04-10 Incyte Corporation Hétérocycles substitués servant d'inhibiteurs de janus kinases
KR101433152B1 (ko) 2006-12-22 2014-08-22 시그마타우 인두스트리에 파르마슈티케 리우니테 에스.피.에이. 안과용 약물의 전달에 유용한 젤
KR20080062876A (ko) 2006-12-29 2008-07-03 주식회사 대웅제약 신규한 항진균성 트리아졸 유도체
WO2008082840A1 (fr) 2006-12-29 2008-07-10 Abbott Laboratories Inhibiteurs de la pim kinase utilisés comme agents chimiothérapeutiques contre le cancer
WO2008082839A2 (fr) 2006-12-29 2008-07-10 Abbott Laboratories Inhibiteurs de la pim kinase comme agents chimiothérapeutiques destinés à lutter contre le cancer
CN101679266B (zh) 2007-03-01 2015-05-06 诺华股份有限公司 Pim激酶抑制剂及其应用方法
EP2137184B1 (fr) 2007-04-03 2013-05-08 Array Biopharma, Inc. Composés imidazo[1,2-a]pyridine utilisés comme inhibiteurs des récepteurs à activité tyrosine kinase
US8188178B2 (en) 2007-05-07 2012-05-29 3M Innovative Properties Company Cold shrinkable article including an epichlorohydrin composition
GB0709031D0 (en) 2007-05-10 2007-06-20 Sareum Ltd Pharmaceutical compounds
WO2008145681A2 (fr) 2007-05-31 2008-12-04 Boehringer Ingelheim International Gmbh Antagonistes des récepteurs ccr2 et utilisations de ceux-ci
GB0710528D0 (en) 2007-06-01 2007-07-11 Glaxo Group Ltd Novel compounds
CL2008001709A1 (es) 2007-06-13 2008-11-03 Incyte Corp Compuestos derivados de pirrolo [2,3-b]pirimidina, moduladores de quinasas jak; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como cancer, psoriasis, artritis reumatoide, entre otras.
DK2740731T3 (en) 2007-06-13 2016-04-11 Incyte Holdings Corp CRYSTALLINE SALTS OF JANUSKINASEINHIBITOREN (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-CYCLOPENTYLPROPANNITRIL
KR101258316B1 (ko) 2007-07-11 2013-04-30 화이자 인코포레이티드 안구 건조증 치료용 약학 조성물 및 방법
JP4792126B2 (ja) 2007-08-01 2011-10-12 ファイザー・インク ピラゾール化合物およびＲａｆ阻害剤としてのその使用
WO2009049028A1 (fr) 2007-10-09 2009-04-16 Targegen Inc. Composés de pyrrolopyrimidine et leur utilisation en tant qu'inhibiteurs des janus kinases
US20110263664A1 (en) 2007-11-15 2011-10-27 Musc Foundation For Research Development Inhibitors of PIM-1 Protein Kinases, Compositions and Methods for Treating Prostate Cancer
WO2009064835A1 (fr) 2007-11-16 2009-05-22 Incyte Corporation 4-pyrazolyl-n-arylpyrimidin-2-amines et 4-pyrazolyl-n-hétéroarylpyrimidin-2-amines en tant qu'inhibiteurs de janus kinase
GB0723815D0 (en) 2007-12-05 2008-01-16 Glaxo Group Ltd Compounds
EP2231689B1 (fr) 2008-01-18 2016-07-20 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Nouveaux nucléosides 7-déazapurine cytostatiques
MY158994A (en) 2008-02-04 2016-11-30 Mercury Therapeutics Inc Ampk modulators
PE20091577A1 (es) 2008-03-03 2009-11-05 Novartis Ag Inhibidores de cinasa pim y metodos para su uso
BRPI0909040B8 (pt) 2008-03-11 2021-05-25 Incyte Holdings Corp derivados de azetidina e ciclobutano, seus usos, e composição
KR101408517B1 (ko) 2008-03-21 2014-06-17 노파르티스 아게 신규한 헤테로시클릭 화합물 및 그의 용도
WO2009155156A1 (fr) 2008-06-18 2009-12-23 Merck & Co., Inc. Inhibiteurs de janus kinases
KR102080429B1 (ko) 2008-06-26 2020-02-21 안테리오스, 인코퍼레이티드 경피 운반
TWI461423B (zh) 2008-07-02 2014-11-21 Astrazeneca Ab 用於治療Pim激酶相關病狀及疾病之噻唑啶二酮化合物
FR2933409B1 (fr) 2008-07-03 2010-08-27 Centre Nat Rech Scient NOUVEAUX PYRROLO °2,3-a! CARBAZOLES ET LEUR UTILISATION COMME INHIBITEURS DES KINASES PIM
TWI496779B (zh) 2008-08-19 2015-08-21 Array Biopharma Inc 作為ｐｉｍ激酶抑制劑之三唑吡啶化合物
WO2010022081A1 (fr) 2008-08-19 2010-02-25 Array Biopharma Inc. Composés de triazolopyridine comme inhibiteurs des kinases pim
BRPI0917459B1 (pt) 2008-08-20 2017-09-12 Zoetis Services Llc N-methyl-1- [trans-4- [methyl (7h-pyrrol [2,3-d] pyridol [2,3-d] pyrimidine compounds, use of these in therapy and crystalline a form of n-methyl- pyrimidin-4-yl) amino] cyclohexyl} methanosulphonamide
JP5584215B2 (ja) 2008-09-02 2014-09-03 ノバルティス アーゲー ヘテロ環ｐｉｍキナーゼ阻害剤
BRPI0918496A2 (pt) 2008-09-02 2019-09-24 Novartis Ag composto inibidor bicíclico de quinase, uso do mesmo, composição farmacêutica e método para inibir a atividade da quinase pim em uma célula
MX2011002365A (es) 2008-09-02 2011-04-04 Novartis Ag Derivados de picolinamida como inhibidres de cinasa.
CL2009001884A1 (es) 2008-10-02 2010-05-14 Incyte Holdings Corp Uso de 3-ciclopentil-3-[4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)propanonitrilo, inhibidor de janus quinasa, y uso de una composición que lo comprende para el tratamiento del ojo seco.
US20110183958A1 (en) 2008-10-17 2011-07-28 Merck Frosst Canada Ltd. Azetidine derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase
JOP20190230A1 (ar) 2009-01-15 2017-06-16 Incyte Corp طرق لاصلاح مثبطات انزيم jak و المركبات الوسيطة المتعلقة به
EP2210890A1 (fr) 2009-01-19 2010-07-28 Almirall, S.A. Dérivés d'oxadiazoles en tant qu'agonistes du récepteur S1P1
US8263601B2 (en) 2009-02-27 2012-09-11 Concert Pharmaceuticals, Inc. Deuterium substituted xanthine derivatives
AU2010249443B2 (en) 2009-05-22 2015-08-13 Incyte Holdings Corporation 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octane- or heptane-nitrile as JAK inhibitors
MY156727A (en) 2009-05-22 2016-03-15 Incyte Corp N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
UA110324C2 (en) 2009-07-02 2015-12-25 Genentech Inc Jak inhibitory compounds based on pyrazolo pyrimidine
EP2451813B1 (fr) 2009-07-08 2014-10-01 Leo Pharma A/S Composés hétérocycliques en tant qu inhibiteurs du récepteur jak et de la protéine tyrosine kinase
US20120157500A1 (en) 2009-08-24 2012-06-21 Weikang Tao Jak inhibition blocks rna interference associated toxicities
TW201111385A (en) 2009-08-27 2011-04-01 Biocryst Pharm Inc Heterocyclic compounds as janus kinase inhibitors
TW201113285A (en) 2009-09-01 2011-04-16 Incyte Corp Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
SG10201405568UA (en) 2009-09-08 2014-11-27 Hoffmann La Roche 4-substituted pyridin-3-yl-carboxamide compounds and methods of use
EP2305660A1 (fr) 2009-09-25 2011-04-06 Almirall, S.A. Nouveaux dérivés de thiadiazole
KR101921850B1 (ko) 2009-10-09 2018-11-23 인사이트 홀딩스 코포레이션 3-（4-（7Ｈ-피롤로〔2,3-ｄ〕피리미딘-4-일）-1Ｈ-피라졸-1-일）-3-사이클로펜틸프로판니트릴의 하이드록실, 케토 및 글루쿠로나이드 유도체
CA2775009A1 (fr) 2009-10-20 2011-04-28 Cellzome Limited Analogues d'heterocyclyl pyrazolopyrimidine en tant qu'inhibiteurs de jak
US8671402B2 (en) 2009-11-09 2014-03-11 Bank Of America Corporation Network-enhanced control of software updates received via removable computer-readable medium
EP2332917B1 (fr) 2009-11-11 2012-08-01 Sygnis Bioscience GmbH & Co. KG Composés pour l'inhibition de kinase PIM et pour le traitement des tumeurs
EP2504030A4 (fr) 2009-11-24 2013-06-26 Alderbio Holdings Llc Antagonistes de l'il-6 destinés à faire augmenter l'albumine et/ou à faire baisser la crp
EP2506852A4 (fr) 2009-12-04 2013-06-19 Univ Texas Traitement à l'interféron en combinaison avec un blocage de l'activation de stat3
ES2461967T3 (es) 2009-12-18 2014-05-21 Pfizer Inc. Compuestos de pirrolo[2,3-d]pirimidina
CN102712640A (zh) 2010-01-12 2012-10-03 弗·哈夫曼-拉罗切有限公司 三环杂环化合物、其组合物和应用方法
JP2013518882A (ja) 2010-02-05 2013-05-23 ファイザー・インク ＪＡＫ阻害剤としてのピロロ［２，３−ｄ］ピリミジン尿素化合物
SA111320200B1 (ar) 2010-02-17 2014-02-16 ديبيوفارم اس ايه مركبات ثنائية الحلقة واستخداماتها كمثبطات c-src/jak مزدوجة
CA2790070C (fr) 2010-02-18 2018-03-06 Incyte Corporation Derives de cyclobutane et de methylcyclobutane comme inhibiteurs de janus kinases
AU2011224484A1 (en) 2010-03-10 2012-09-27 Incyte Holdings Corporation Piperidin-4-yl azetidine derivatives as JAK1 inhibitors
US8962596B2 (en) 2010-04-14 2015-02-24 Array Biopharma Inc. 5,7-substituted-imidazo[1,2-C]pyrimidines as inhibitors of JAK kinases
EP2390252A1 (fr) 2010-05-19 2011-11-30 Almirall, S.A. Nouveaux dérivés de pyrazole
MY161078A (en) 2010-05-21 2017-04-14 Incyte Holdings Corp Topical formulation for a jak inhibitor
US8637529B2 (en) 2010-06-11 2014-01-28 AbbYie Inc. Pyrazolo[3,4-d]pyrimidine compounds
WO2012003457A1 (fr) 2010-07-01 2012-01-05 Mtm Research Llc Thérapies au moyen d'émulsions fluorochimiques antifibroblastiques
WO2012045010A1 (fr) 2010-09-30 2012-04-05 Portola Pharmaceuticals, Inc. Combinaisons de 4-(3-(2h-1,2,3-triazol-2-yl)phénylamino)-2-((1r,2s)-2-aminocyclohexylamino)pyrimidine-5-carboxamide et de fludarabine
WO2012068440A1 (fr) 2010-11-19 2012-05-24 Incyte Corporation Pyrrolopyridines et pyrrolopyrimidines à substitution hétérocyclique utilisées en tant qu'inhibiteurs des jak
EP2640723A1 (fr) 2010-11-19 2013-09-25 Incyte Corporation Dérivés pyrrolopyridine et pyrrolopyrimidine à substitution cyclobutyle utilisés comme inhibiteurs des jak
SG190950A1 (en) 2010-12-03 2013-07-31 Ym Biosciences Australia Pty Treatment of jak2-mediated conditions
ES2547916T3 (es) 2011-02-18 2015-10-09 Novartis Pharma Ag Terapia de combinación de inhibidores de mTOR/JAK
CN102247368B (zh) 2011-05-19 2013-05-29 安徽永生堂药业有限责任公司 一种复方阿伐斯汀缓释片及其制备方法
CN102218042A (zh) 2011-05-26 2011-10-19 青岛黄海制药有限责任公司 富马酸喹硫平组合物的缓释片剂及其制备方法
KR20140040819A (ko) 2011-06-20 2014-04-03 인사이트 코포레이션 Ｊａｋ 저해제로서의 아제티디닐 페닐, 피리딜 또는 피라지닐 카르복스아미드 유도체
WO2013007768A1 (fr) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Composés hétérocycliques tricycliques, compositions et procédés d'utilisation de ces composés comme inhibiteurs des jak
WO2013007765A1 (fr) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Composés tricycliques fusionnés utilisés en tant qu'inhibiteurs des janus kinases
HK1198579A1 (en) 2011-08-10 2015-04-30 Novartis Pharma Ag Jak p13k/mtor combination therapy
TW201313721A (zh) 2011-08-18 2013-04-01 Incyte Corp 作為ｊａｋ抑制劑之環己基氮雜環丁烷衍生物
UA111854C2 (uk) 2011-09-07 2016-06-24 Інсайт Холдінгс Корпорейшн Способи і проміжні сполуки для отримання інгібіторів jak
WO2013173720A1 (fr) 2012-05-18 2013-11-21 Incyte Corporation Dérivés de pyrrolopyridine et de pyrrolopyrimidine substitués par un pipéridinylcyclobutyle à titre d'inhibiteurs jak
US10155987B2 (en) 2012-06-12 2018-12-18 Dana-Farber Cancer Institute, Inc. Methods of predicting resistance to JAK inhibitor therapy
EA201492287A1 (ru) 2012-06-15 2015-07-30 Консерт Фармасьютикалс, Инк. Дейтерированные производные руксолитиниба
WO2014016396A1 (fr) 2012-07-27 2014-01-30 Ratiopharm Gmbh Formes galéniques orales destinées à une libération modifiée comprenant du ruxolitinib
CN102772384A (zh) 2012-08-07 2012-11-14 四川百利药业有限责任公司 一种盐酸米诺环素缓释片及其制备方法
WO2014036016A1 (fr) 2012-08-31 2014-03-06 Principia Biopharma Inc. Dérivés de benzimidazole en tant qu'inhibiteurs d'itk
UA117572C2 (uk) 2012-11-01 2018-08-27 Інсайт Холдинґс Корпорейшн Трициклічні конденсовані похідні тіофену як інгібітори jak
PH12020551186B1 (en) 2012-11-15 2024-03-20 Incyte Holdings Corp Sustained-release dosage forms of ruxolitinib
JP6397831B2 (ja) 2013-03-06 2018-09-26 インサイト・ホールディングス・コーポレイションＩｎｃｙｔｅ Ｈｏｌｄｉｎｇｓ Ｃｏｒｐｏｒａｔｉｏｎ Ｊａｋ阻害剤の製造方法及びその中間体
TWI719401B (zh) 2013-05-17 2021-02-21 美商英塞特公司 作為jak抑制劑之聯吡唑衍生物
KR20160045081A (ko) 2013-08-07 2016-04-26 인사이트 코포레이션 Jak1 억제제용 지속 방출 복용 형태
TW201529074A (zh) 2013-08-20 2015-08-01 Incyte Corp 在ｃ-反應蛋白含量較高之實體腫瘤患者中的存活益處
CN106456773A (zh) 2014-02-28 2017-02-22 因赛特公司 用于治疗骨髓增生异常综合征的jak1抑制剂
LT3129021T (lt) 2014-04-08 2020-12-10 Incyte Corporation B ląstelių piktybiškumo gydymas jak ir pi3k inhibitorių deriniu
MX2016014192A (es) 2014-04-30 2017-05-01 Incyte Corp Procesos para preparar un inhibidor de cinasas de janus 1 (jak1) y nuevas formas de este.
WO2015184087A2 (fr) 2014-05-28 2015-12-03 Institute For Myeloma & Bone Cancer Research Effets anti-cancéreux d'inhibiteurs de jak2 en combinaison avec des dérivés de thalidomide et des glucocorticoïdes
WO2015184305A1 (fr) 2014-05-30 2015-12-03 Incyte Corporation Traitement de la leucémie neutrophile chronique (cnl) et de la leucémie myéloïde chronique atypique (acml) par des inhibiteurs de jak1
US10766900B2 (en) 2017-12-29 2020-09-08 Formosa Laboratories, Inc. Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof
AU2020219797B2 (en) 2019-02-06 2025-10-16 Sun Pharmaceutical Industries, Inc. Process for preparing enantiomerically enriched jak inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

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